143 results on '"Dolcet X"'
Search Results
2. Cyclin D1 interacts and collaborates with Ral GTPases enhancing cell detachment and motility
- Author
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Fernández, R M H, Ruiz-Miró, M, Dolcet, X, Aldea, M, and Garí, E
- Published
- 2011
- Full Text
- View/download PDF
3. Molecular pathology of endometrial carcinoma: practical aspects from the diagnostic and therapeutic viewpoints
- Author
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Llobet, D., Pallares, J., Yeramian, A., Santacana, M., Eritja, N., Velasco, A., Dolcet, X., and Matias-Guiu, X.
- Subjects
Endometrial cancer -- Diagnosis ,Apoptosis -- Research ,Apoptosis -- Physiological aspects ,Pathology, Molecular -- Analysis ,Health - Published
- 2009
4. CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells
- Author
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Llobet, D, Eritja, N, Encinas, M, Llecha, N, Yeramian, A, Pallares, J, Sorolla, A, Gonzalez-Tallada, F J, Matias-Guiu, X, and Dolcet, X
- Published
- 2008
- Full Text
- View/download PDF
5. A novel inducible model for the study of PTEN-induced carcinogenesis: P13r-104
- Author
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Barbeito, C. M., Eritja, N., Bergadà, L., Gatius, S., Santacana, M., Matias-Guiu, X., and Dolcet, X.
- Published
- 2012
6. PTEN deficiency enhances estradiol proliferation on endometrial epithelial glands: P07r-13
- Author
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Sanchez, N. E., Mirantes, C., Llobet, D., Yeramian, A., Matias-Guiu, X., and Dolcet, X.
- Published
- 2012
7. P172 Preclinical evidences of the therapeutic potential of ABTL0812 in endometrial cancer
- Author
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Gil-Moreno, A, primary, Felip, I, additional, Moiola, CP, additional, Megino-Luque, C, additional, Lopez-Gil, C, additional, Cabrera, S, additional, Solé-Sánchez, S, additional, Muñoz-Guardiola, P, additional, Megias-Roda, E, additional, Pérez-Montoyo, H, additional, Alfon, J, additional, Yeste-Velasco, MY-V, additional, Santacana, M, additional, Dolcet, X, additional, Reques, A, additional, Oaknin, A, additional, Rodríguez-Freixinos, V, additional, Lizcano, JML, additional, Domènech, C, additional, Matias-Guiu, X, additional, Colas, E, additional, and Eritja, N, additional
- Published
- 2019
- Full Text
- View/download PDF
8. Effect of proteasome inhibitors on proliferation and apoptosis of human cutaneous melanoma-derived cell lines
- Author
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Sorolla, A., Yeramian, A., Dolcet, X., Pérez de Santos, A. M., Llobet, D., Schoenenberger, J. A., Casanova, J. M., Soria, X., Egido, R., Llombart, A., Vilella, R., Matias-Guiu, X., and Marti, R. M.
- Published
- 2008
9. Bioluminescence Imaging to Monitor the Effects of the Hsp90 Inhibitor NVP-AUY922 on NF-kappa B Pathway in Endometrial Cancer
- Author
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Yeramian, A, Garcia, V, Bergada, L, Domingo, M, Santacana, M, Valls, J, Martinez-Alonso, M, Carceller, J, Cussac, A, Dolcet, X, and Matias-Guiu, X
- Subjects
Survival pathways ,immune system diseases ,NF-kappa B ,virus diseases ,Hsp90 ,Endometrial carcinoma ,Bioluminescence - Abstract
In this study, we first aimed to evaluate the effects in vitro and in vivo, of the Hsp90 inhibitor NVP-AUY922, in endometrial cancer (EC). We also aimed to track nuclear factor kappa B (NF-kappa B) signalling, a key pathway involved in endometrial carcinogenesis and to check whether NVP-AUY922 treatment modulates it both in vitro and in vivo. I n vitro effects of NVP-AUY922 on EC cell growth and the signalling pathways were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic assays, Western Blot and luciferase assay. NVP-AUY922 effect on Ishikawa (IK) xenograft growth was evaluated in vivo, and NF-kappa B activity was monitored using bioluminescence imaging. NVP-AUY922 inhibited the growth of three endometrial cell lines tested in vitro. In vivo, NVP-AUY922 reduced tumour growth of 47 % (p = 0.042) compared to control condition. Moreover, the bioluminescence signal of the tumours harbouring IK NF-kappa B-LUC cells was significantly reduced in NVP-AUY922-treated animals compared to untreated ones. NVP-AUY922 reduced EC tumour growth and NF-kappa B signalling both in vitro and in vivo. As therapeutic resistance of EC remains a challenge for oncologists nowadays, we think that NVP-AUY922 represents a valid alternative to conventional chemotherapy, and we believe that this approach for assessing and tracking the activation of NF-kappa B pathway may be of therapeutic benefit.
- Published
- 2016
10. MOLECULAR PROFILING OF CIRCULATING TUMOR CELLS LINKS PLASTICITY TO THE METASTATIC PROCESS IN ENDOMETRIAL CANCER
- Author
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Alonso Alconada, L., Krakstad, C., Trovik, J., Wik, E., Hapangama, D., Coenegrachts, L., Gil-Moreno, A., Colas, E., Dolcet, X., Nijman, H. W., Tjalling Bosse, Green, J. A., Romano, A., Reventos, J., Lopez-Lopez, R., Salvesen, H. B., Amant, F., Matias-Guiu, X., Moreno-Bueno, G., Abal, M., Targeted Gynaecologic Oncology (TARGON), and Translational Immunology Groningen (TRIGR)
- Published
- 2013
11. Epithelial-to-mesenchytnal transition and stem cells in endometrial cancer
- Author
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Mirantes, C, Espinosa, I, Ferrer, I, Dolcet, X, Prat, J, and Matias-Guiu, X
- Subjects
Epithelial-to-mesenchymal transition ,Cancer stem cells ,Endometrial carcinoma ,Somatic stem cells - Abstract
This review article describes the main features of epithelial-to-mesenchymal transition (EMT) and its possible role in understanding myometrial invasion in endometrial carcinoma (EC), as well as the development of malignant mixed Mullerian tumor (MMMT). Moreover, the article discusses the possible role of somatic (SSC) and cancer stem cells (CSC) in EC. Different transcriptional repressors of E-cadherin have been identified in EMT, including Snail and Slug, ZEB1 and ZEB2, and E47 and Twist. The expression of some of these genes is increased at the myoinvasive front and correlates inversely with E-cadherin inmunoreactivity. Whereas the transient occurrence of the EMT phenomenon is important for myometrial invasion in conventional EC, MMMT shows permanent expression of EMT leading to repression of E-cadherin and increased expression of mesenchymal markers including proteins involved in skeletal muscle development. An SSC population, identified as a side population, assessed by the Hoechst dye exclusion test has been identified in human endometrium. CSCs have been defined in analogy to SSC as cancer cells that have the capacity to self-renew, which means undergoing divisions that allow the generation of more identical CSCs and give rise to the variety of more differentiated cells found in the malignancy. Although published data show that CD133(+) cells retain the characteristics of CSC, there is no conclusive evidence showing that CD133 is the universal marker for EC stem cells. Finally, a possible role for endometrial stem cells in the development of ovarian endometriosis and ovarian endometrioid carcinoma is commented. (C) 2013 Elsevier Inc. All rights reserved.
- Published
- 2013
12. Endometrial carcinoma: molecular alterations involved in tumor development and progression
- Author
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Yeramian, A, primary, Moreno-Bueno, G, additional, Dolcet, X, additional, Catasus, L, additional, Abal, M, additional, Colas, E, additional, Reventos, J, additional, Palacios, J, additional, Prat, J, additional, and Matias-Guiu, X, additional
- Published
- 2012
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- View/download PDF
13. The Canonical Nuclear Factor- B Pathway Regulates Cell Survival in a Developmental Model of Spinal Cord Motoneurons
- Author
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Mincheva, S., primary, Garcera, A., additional, Gou-Fabregas, M., additional, Encinas, M., additional, Dolcet, X., additional, and Soler, R. M., additional
- Published
- 2011
- Full Text
- View/download PDF
14. 414 ETV5 transcription factor is upregulated in ovarian cancer and has a role in tumour progression
- Author
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Llauradó, M., primary, Abal, M., additional, Castellví, J., additional, Cabrera, S., additional, Gil-Moreno, A., additional, Doll, A., additional, Dolcet, X., additional, Matias-Guiu, X., additional, Reventós, J., additional, and Ruiz, A., additional
- Published
- 2010
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- View/download PDF
15. The multikinase inhibitor Sorafenib induces apoptosis and sensitises endometrial cancer cells to TRAIL by different mechanisms
- Author
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Llobet, D., primary, Eritja, N., additional, Yeramian, A., additional, Pallares, J., additional, Sorolla, A., additional, Domingo, M., additional, Santacana, M., additional, Gonzalez-Tallada, F.J., additional, Matias-Guiu, X., additional, and Dolcet, X., additional
- Published
- 2010
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16. Expression of Somatostatin Receptors in Human Melanoma Cell Lines: Effect of Two Different Somatostatin Analogues, Octreotide and SOM230, on Cell Proliferation
- Author
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Martinez-Alonso, M, primary, Llecha, N, additional, Mayorga, ME, additional, Sorolla, A, additional, Dolcet, X, additional, Sanmartin, V, additional, Abal, L, additional, Casanova, JM, additional, Baradad, M, additional, Yeramian, A, additional, Egido, R, additional, Puig, S, additional, Vilella, R, additional, Matias-Guiu, X, additional, and Marti, RM, additional
- Published
- 2009
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17. Targeting the extrinsic apoptotic pathway in endometrial carcinoma cell lines and tumor cell explants
- Author
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Matias-guiu, X., primary, Dolcet, X., additional, Llobet, D., additional, Poveda, A., additional, Pallares, J., additional, Eritia, N., additional, Yeramian, A., additional, Sorolla, A., additional, Ortega, E., additional, and Llombart-Cussac, A., additional
- Published
- 2009
- Full Text
- View/download PDF
18. Molecular pathology of endometrial carcinoma: practical aspects from the diagnostic and therapeutic viewpoints
- Author
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Llobet, D, primary, Pallares, J, additional, Yeramian, A, additional, Santacana, M, additional, Eritja, N, additional, Velasco, A, additional, Dolcet, X, additional, and Matias-Guiu, X, additional
- Published
- 2008
- Full Text
- View/download PDF
19. Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI 3-K, in neurotrophic factor-induced survival of sympathetic neurons
- Author
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Encinas, M, primary, Rozen, E J, additional, Dolcet, X, additional, Jain, S, additional, Comella, J X, additional, Milbrandt, J, additional, and Johnson, E M, additional
- Published
- 2008
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- View/download PDF
20. CK2 controls TRAIL and Fas sensitivity by regulating FLIP levels in endometrial carcinoma cells
- Author
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Llobet, D, primary, Eritja, N, additional, Encinas, M, additional, Llecha, N, additional, Yeramian, A, additional, Pallares, J, additional, Sorolla, A, additional, Gonzalez-Tallada, F J, additional, Matias-Guiu, X, additional, and Dolcet, X, additional
- Published
- 2007
- Full Text
- View/download PDF
21. PIK3CA gene mutations in endometrial carcinoma. Correlation with PTEN and K-RAS alterations☆
- Author
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VELASCO, A, primary, BUSSAGLIA, E, additional, PALLARES, J, additional, DOLCET, X, additional, LLOBET, D, additional, ENCINAS, M, additional, LLECHA, N, additional, PALACIOS, J, additional, PRAT, J, additional, and MATIASGUIU, X, additional
- Published
- 2006
- Full Text
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22. FISH analysis of PTEN in endometrial carcinoma. Comparison with SNP arrays and MLPA
- Author
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Maiques O, Cuevas D, Da, García Dios, Coenegrachts L, Santacana M, ANA VELASCO, Romero M, Sónia G, Lambrechts D, Dolcet X, Amant F, and Matias-Guiu X
23. Multiple endocrine defects in adult-onset Sprouty1/2/4 triple knockout mice.
- Author
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Altés G, Olomí A, Perramon-Güell A, Hernández S, Casanovas A, Pérez A, Díaz-Tocados JM, Valdivielso JM, Megino C, Navaridas R, Matias-Guiu X, Klein OD, Egea J, Dolcet X, Yeramian A, and Encinas M
- Subjects
- Animals, Mice, Intracellular Signaling Peptides and Proteins genetics, Female, Male, Endocrine System Diseases genetics, Endocrine System Diseases metabolism, Nerve Tissue Proteins, Protein Serine-Threonine Kinases, Mice, Knockout, Membrane Proteins genetics, Membrane Proteins metabolism, Phosphoproteins genetics, Phosphoproteins metabolism, Fibroblast Growth Factor-23, Adaptor Proteins, Signal Transducing genetics
- Abstract
Genes of the Sprouty family (Spry1-4) are feedback inhibitors of receptor tyrosine kinases, especially of Ret and the FGF receptors. As such, they play distinct and overlapping roles in embryo morphogenesis and are considered to be tumor suppressors in adult life. Genetic experiments in mice have defined in great detail the role of these genes during embryonic development, however their function in adult mice is less clearly established. Here we generate adult-onset, whole body Spry1/2/4 triple knockout mice. Tumor incidence in triple mutant mice is comparable to that of wild type littermates of up to one year of age, indicating that Sprouty loss per se is not sufficient to initiate tumorigenesis. On the other hand, triple knockout mice do not gain weight as they age, show less visceral fat, and have lower plasma glucose levels than wild type littermates, despite showing similar food intake and slightly reduced motor function. They also show alopecia, eyelid inflammation, and mild hyperthyroidism. Finally, triple knockout mice present phosphaturia and hypophosphatemia, suggesting exacerbated signaling downstream of FGF23. In conclusion, triple knockout mice develop a series of endocrine abnormalities but do not show increased tumor incidence., (© 2024. The Author(s).)
- Published
- 2024
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- View/download PDF
24. Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression.
- Author
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Lorite NP, Apostolova S, Guasch-Vallés M, Pryer A, Unzueta F, Freire R, Solé-Soler R, Pedraza N, Dolcet X, Garí E, Agell N, Taylor EM, Colomina N, and Torres-Rosell J
- Subjects
- Humans, Chromosomal Proteins, Non-Histone metabolism, Chromosomal Proteins, Non-Histone genetics, Protein Domains, Protein Stability, Mutation, Cell Line, DNA Helicases, Cell Cycle Proteins metabolism, Cell Cycle Proteins genetics, Genomic Instability, DNA Replication
- Abstract
The Smc5/6 complex is a highly conserved molecular machine involved in the maintenance of genome integrity. While its functions largely depend on restraining the fork remodeling activity of Mph1 in yeast, the presence of an analogous Smc5/6-FANCM regulation in humans remains unknown. We generated human cell lines harboring mutations in the NSE1 subunit of the Smc5/6 complex. Point mutations or truncations in the RING domain of NSE1 result in drastically reduced Smc5/6 protein levels, with differential contribution of the two zinc-coordinating centers in the RING. In addition, nse1-RING mutant cells display cell growth defects, reduced replication fork rates, and increased genomic instability. Notably, our findings uncover a synthetic sick interaction between Smc5/6 and FANCM and show that Smc5/6 controls fork progression and chromosome disjunction in a FANCM-independent manner. Overall, our study demonstrates that the NSE1 RING domain plays vital roles in Smc5/6 complex stability and fork progression through pathways that are not evolutionary conserved., (© 2024. The Author(s).)
- Published
- 2024
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25. Sprouty1 is a broad mediator of cellular senescence.
- Author
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Anerillas C, Perramon-Güell A, Altés G, Cuesta S, Vaquero M, Olomí A, Rodríguez-Barrueco R, Llobet-Navàs D, Egea J, Dolcet X, Yeramian A, and Encinas M
- Subjects
- Animals, Mice, Humans, Adaptor Proteins, Signal Transducing metabolism, Adaptor Proteins, Signal Transducing genetics, Phosphoproteins metabolism, Phosphoproteins genetics, p38 Mitogen-Activated Protein Kinases metabolism, Intracellular Signaling Peptides and Proteins metabolism, Intracellular Signaling Peptides and Proteins genetics, MAP Kinase Signaling System, Wound Healing, Cellular Senescence, Membrane Proteins metabolism, Membrane Proteins genetics, Fibroblasts metabolism
- Abstract
Genes of the Sprouty family (Spry1-4) restrain signaling by certain receptor tyrosine kinases. Consequently, these genes participate in several developmental processes and function as tumor suppressors in adult life. Despite these important roles, the biology of this family of genes still remains obscure. Here we show that Sprouty proteins are general mediators of cellular senescence. Induction of cellular senescence by several triggers in vitro correlates with upregulation of Sprouty protein levels. More importantly, overexpression of Sprouty genes is sufficient to cause premature cellular senescence, via a conserved N-terminal tyrosine (Tyrosine 53 of Sprouty1). Accordingly, fibroblasts from knockin animals lacking that tyrosine escape replicative senescence. In vivo, heterozygous knockin mice display delayed induction of cellular senescence during cutaneous wound healing and upon chemotherapy-induced cellular senescence. Unlike other functions of this family of genes, induction of cellular senescence appears to be independent of activation of the ERK1/2 pathway. Instead, we show that Sprouty proteins induce cellular senescence upstream of the p38 pathway in these in vitro and in vivo paradigms., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
26. Metformin exhibits antineoplastic effects on Pten-deficient endometrial cancer by interfering with TGF-β and p38/ERK MAPK signalling.
- Author
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Ruiz-Mitjana A, Vidal-Sabanés M, Navaridas R, Perramon-Güell A, Yeramian A, Nicholson-Sabaté N, Egea J, Encinas M, Matias-Guiu X, and Dolcet X
- Subjects
- Humans, Female, Animals, Mice, Transforming Growth Factor beta pharmacology, Cell Proliferation, Metformin pharmacology, Metformin therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Endometrial Neoplasms pathology
- Abstract
Metformin is a widespread antidiabetic agent that is commonly used as a treatment against type 2 diabetes mellitus patients. Regarding its therapeutic potential, multiple studies have concluded that Metformin exhibits antineoplastic activity on several types of cancer, including endometrial carcinoma. Although Metformin's antineoplastic activity is well documented, its cellular and molecular anticancer mechanisms are still a matter of controversy because a plethora of anticancer mechanisms have been proposed for different cancer cell types. In this study, we addressed the cellular and molecular mechanisms of Metformin's antineoplastic activity by using both in vitro and in vivo studies of Pten-loss driven carcinoma mouse models. In vivo, Metformin reduced endometrial neoplasia initiated by Pten-deficiency. Our in vitro studies using Pten-deficient endometrial organoids focused on both cellular and molecular levels in Metformin's tumor suppressive action. At cellular level, we showed that Metformin is involved in not only the proliferation of endometrial epithelial cells but also their regulation via a variety of mechanisms of epithelial-to-mesenchymal transition (EMT) as well as TGF-β-induced apoptosis. At the molecular level, Metformin was shown to affect the TGF-β signalling., a widely known signal that plays a pivotal role in endometrial carcinogenesis. In this respect, Metformin restored TGF-β-induced apoptosis of Pten-deficient endometrial organoids through a p38-dependent mechanism and inhibited TGF-β-induced EMT on no-polarized endometrial epithelial cells by inhibiting ERK/MAPK signalling. These results provide new insights into the link between the cellular and molecular mechanism for Metformin's antineoplastic activity in Pten-deficient endometrial cancers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2023
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27. In Vivo Intra-Uterine Delivery of TAT-Fused Cre Recombinase and CRISPR/Cas9 Editing System in Mice Unveil Histopathology of Pten/p53-Deficient Endometrial Cancers.
- Author
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Navaridas R, Vidal-Sabanés M, Ruiz-Mitjana A, Altés G, Perramon-Güell A, Yeramian A, Egea J, Encinas M, Gatius S, Matias-Guiu X, and Dolcet X
- Subjects
- Humans, Female, Mice, Animals, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Epithelial-Mesenchymal Transition, CRISPR-Cas Systems genetics, Endometrial Neoplasms genetics, Endometrial Neoplasms metabolism, Endometrial Neoplasms pathology, Uterine Neoplasms genetics, Uterine Neoplasms pathology, Carcinosarcoma genetics, Carcinosarcoma pathology
- Abstract
Phosphatase and TENsin homolog (Pten) and p53 are two of the most frequently mutated tumor suppressor genes in endometrial cancer. However, the functional consequences and histopathological manifestation of concomitant p53 and Pten loss of function alterations in the development of endometrial cancer is still controversial. Here, it is demonstrated that simultaneous Pten and p53 deletion is sufficient to cause epithelial to mesenchymal transition phenotype in endometrial organoids. By a novel intravaginal delivery method using HIV1 trans-activator of transcription cell penetrating peptide fused with a Cre recombinase protein (TAT-Cre), local ablation of both p53 and Pten is achieved specifically in the uterus. These mice developed high-grade endometrial carcinomas and a high percentage of uterine carcinosarcomas resembling those found in humans. To further demonstrate that carcinosarcomas arise from epithelium, double Pten/p53 deficient epithelial cells are mixed with wild type stromal and myometrial cells and subcutaneously transplanted to Scid mice. All xenotransplants resulted in the development of uterine carcinosarcomas displaying high nuclear pleomorphism and metastatic potential. Accordingly, in vivo CRISPR/Cas9 disruption of Pten and p53 also triggered the development of metastatic carcinosarcomas. The results unfadingly demonstrate that simultaneous deletion of p53 and Pten in endometrial epithelial cells is enough to trigger epithelial to mesenchymal transition that is consistently translated to the formation of uterine carcinosarcomas in vivo., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)
- Published
- 2023
- Full Text
- View/download PDF
28. Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer.
- Author
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Cassier PA, Navaridas R, Bellina M, Rama N, Ducarouge B, Hernandez-Vargas H, Delord JP, Lengrand J, Paradisi A, Fattet L, Garin G, Gheit H, Dalban C, Pastushenko I, Neves D, Jelin R, Gadot N, Braissand N, Léon S, Degletagne C, Matias-Guiu X, Devouassoux-Shisheboran M, Mery-Lamarche E, Allard J, Zindy E, Decaestecker C, Salmon I, Perol D, Dolcet X, Ray-Coquard I, Blanpain C, Bernet A, and Mehlen P
- Subjects
- Animals, Female, Humans, Mice, Biopsy, Carboplatin administration & dosage, Carboplatin pharmacology, Carboplatin therapeutic use, Disease Models, Animal, Drug Resistance, Neoplasm drug effects, Gene Expression Profiling, Paclitaxel administration & dosage, Paclitaxel pharmacology, Paclitaxel therapeutic use, RNA-Seq, Single-Cell Gene Expression Analysis, Tumor Microenvironment drug effects, Endometrial Neoplasms drug therapy, Endometrial Neoplasms genetics, Endometrial Neoplasms immunology, Endometrial Neoplasms pathology, Epithelial-Mesenchymal Transition drug effects, Netrin-1 antagonists & inhibitors, Antibodies, Monoclonal, Humanized pharmacology
- Abstract
Netrin-1 is upregulated in cancers as a protumoural mechanism
1 . Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care2 , we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments., (© 2023. The Author(s).)- Published
- 2023
- Full Text
- View/download PDF
29. Transient and DNA-free in vivo CRISPR/Cas9 genome editing for flexible modeling of endometrial carcinogenesis.
- Author
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Navaridas R, Vidal-Sabanés M, Ruiz-Mitjana A, Perramon-Güell A, Megino-Luque C, Llobet-Navas D, Matias-Guiu X, Egea J, Encinas M, Bardia L, Colombelli J, and Dolcet X
- Subjects
- Humans, DNA, Gene Editing, CRISPR-Cas Systems
- Published
- 2023
- Full Text
- View/download PDF
30. The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival.
- Author
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Diéguez-Martínez N, Espinosa-Gil S, Yoldi G, Megías-Roda E, Bolinaga-Ayala I, Viñas-Casas M, Gorgisen G, Domingo-Ortí I, Pérez-Montoyo H, Bayascas JR, Colas E, Dolcet X, and Lizcano JM
- Subjects
- Animals, Carboplatin, Cell Proliferation, Cytokines metabolism, Epidermal Growth Factor metabolism, Female, Humans, MAP Kinase Kinase 5 genetics, MAP Kinase Kinase 5 metabolism, MAP Kinase Signaling System, Mice, Mice, Nude, Paclitaxel pharmacology, Paclitaxel therapeutic use, Endometrial Neoplasms genetics, NF-kappa B genetics, NF-kappa B metabolism
- Abstract
Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
31. A dominant negative mutation uncovers cooperative control of caudal Wolffian duct development by Sprouty genes.
- Author
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Altés G, Vaquero M, Cuesta S, Anerillas C, Macià A, Espinet C, Ribera J, Bellusci S, Klein OD, Yeramian A, Dolcet X, Egea J, and Encinas M
- Subjects
- Animals, Female, Male, Mammals, Mice, Mice, Knockout, Mutation genetics, Signal Transduction, Tyrosine, Organogenesis, Wolffian Ducts
- Abstract
The Wolffian ducts (WD) are paired epithelial tubules central to the development of the mammalian genitourinary tract. Outgrowths from the WD known as the ureteric buds (UB) generate the collecting ducts of the kidney. Later during development, the caudal portion of the WD will form the vas deferens, epididymis and seminal vesicle in males, and will degenerate in females. While the genetic pathways controlling the development of the UB are firmly established, less is known about those governing development of WD portions caudal to the UB. Sprouty proteins are inhibitors of receptor tyrosine kinase (RTK) signaling in vivo. We have recently shown that homozygous mutation of a conserved tyrosine (Tyr53) of Spry1 results in UB defects indistinguishable from that of Spry1 null mice. Here, we show that heterozygosity for the Spry1 Y53A allele causes caudal WD developmental defects consisting of ectopically branched seminal vesicles in males and persistent WD in females, without affecting kidney development. Detailed analysis reveals that this phenotype also occurs in Spry1
+/- mice but with a much lower penetrance, indicating that removal of tyrosine 53 generates a dominant negative mutation in vivo. Supporting this notion, concomitant deletion of one allele of Spry1 and Spry2 also recapitulates the genital phenotype of Spry1Y53A/+ mice with high penetrance. Mechanistically, we show that unlike the effects of Spry1 in kidney development, these caudal WD defects are independent of Ret signaling, but can be completely rescued by lowering the genetic dosage of Fgf10. In conclusion, mutation of tyrosine 53 of Spry1 generates a dominant negative allele that uncovers fine-tuning of caudal WD development by Sprouty genes., (© 2022. The Author(s).)- Published
- 2022
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- View/download PDF
32. Lack of extracellular matrix switches TGF-β induced apoptosis of endometrial cells to epithelial to mesenchymal transition.
- Author
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Ruiz-Mitjana A, Navaridas R, Vidal-Sabanés M, Perramon-Güell A, Yeramian A, Felip I, Eritja N, Egea J, Encinas M, Matias-Guiu X, and Dolcet X
- Subjects
- Apoptosis drug effects, Carcinogenesis metabolism, Endometrium metabolism, Epithelial Cells, Female, Humans, Epithelial-Mesenchymal Transition, Extracellular Matrix metabolism, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta pharmacology
- Abstract
The extracellular matrix and the correct establishment of epithelial cell polarity plays a critical role in epithelial cell homeostasis and cell polarity. In addition, loss of tissue structure is a hallmark of carcinogenesis. In this study, we have addressed the role of extracellular matrix in the cellular responses to TGF-β. It is well known that TGF-β is a double-edged sword: it acts as a tumor suppressor in normal epithelial cells, but conversely has tumor-promoting effects in tumoral cells. However, the factors that determine cellular outcome in response to TGF-β remain controversial. Here, we have demonstrated that the lack of extracellular matrix and consequent loss of cell polarity inhibits TGF-β-induced apoptosis, observed when endometrial epithelial cells are polarized in presence of extracellular matrix. Rather, in absence of extracellular matrix, TGF-β-treated endometrial epithelial cells display features of epithelial-to-mesenchymal transition. We have also investigated the molecular mechanism of such a switch in cellular response. On the one hand, we found that the lack of Matrigel results in increased AKT signaling which is sufficient to inhibit TGF-β-induced apoptosis. On the other hand, we demonstrate that TGF-β-induced epithelial-to-mesenchymal transition requires ERK and SMAD2/3 activation. In summary, we demonstrate that loss of cell polarity changes the pro-apoptotic function of TGF-β to tumor-associated phenotype such as epithelial-to-mesenchymal transition. These results may be important for understanding the dual role of TGF-β in normal versus tumoral cells., (© 2022. The Author(s).)
- Published
- 2022
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33. Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma.
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Cemeli T, Guasch-Vallés M, Ribes-Santolaria M, Ibars E, Navaridas R, Dolcet X, Pedraza N, Colomina N, Torres-Rosell J, Ferrezuelo F, Herreros J, and Garí E
- Subjects
- Animals, Cell Proliferation, Down-Regulation, GTP Phosphohydrolases, Humans, Mice, Glioblastoma genetics
- Abstract
Glioblastoma (GBM) is the most common tumor in the central nervous system in adults. This neoplasia shows a high capacity of growth and spreading to the surrounding brain tissue, hindering its complete surgical resection. Therefore, the finding of new antitumor therapies for GBM treatment is a priority. We have previously described that cyclin D1-CDK4 promotes GBM dissemination through the activation of the small GTPases RalA and RalB. In this paper, we show that RalB GTPase is upregulated in primary GBM cells. We found that the downregulation of Ral GTPases, mainly RalB, prevents the proliferation of primary GBM cells and triggers a senescence-like response. Moreover, downregulation of RalA and RalB reduces the viability of GBM cells growing as tumorspheres, suggesting a possible role of these GTPases in the survival of GBM stem cells. By using mouse subcutaneous xenografts, we have corroborated the role of RalB in GBM growth in vivo. Finally, we have observed that the knockdown of RalB also inhibits cell growth in temozolomide-resistant GBM cells. Overall, our work shows that GBM cells are especially sensitive to Ral-GTPase availability. Therefore, we propose that the inactivation of Ral-GTPases may be a reliable therapeutic approach to prevent GBM progression and recurrence.
- Published
- 2022
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34. Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor: Role of Lipid Metabolism.
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Crespo-Masip M, Perez-Gomez A, Garcia-Carrasco A, Jover R, Guzmán C, Dolcet X, Ibarz M, Martínez C, Eritja À, Diaz-Tocados JM, and Valdivielso JM
- Subjects
- Animals, Humans, Insulin metabolism, Lipid Metabolism, Mice, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Receptor, Insulin genetics, Receptor, Insulin metabolism, Vitamin D metabolism, Vitamins, Hypoglycemia, Insulin Resistance, Vitamin D Deficiency complications, Vitamin D Deficiency metabolism
- Abstract
Vitamin D (VD) deficiency has been associated with cancer and diabetes. Insulin signaling through the insulin receptor (IR) stimulates cellular responses by activating the PI3K/AKT pathway. PTEN is a tumor suppressor and a negative regulator of the pathway. Its absence enhances insulin signaling leading to hypoglycemia, a dangerous complication found after insulin overdose. We analyzed the effect of VD signaling in a model of overactivation of the IR. We generated inducible double KO (DKO) mice for the VD receptor (VDR) and PTEN. DKO mice showed severe hypoglycemia, lower total cholesterol and increased mortality. No macroscopic tumors were detected. Analysis of the glucose metabolism did not show clear differences that would explain the increased mortality. Glucose supplementation, either systemically or directly into the brain, did not enhance DKO survival. Lipidic liver metabolism was altered as there was a delay in the activation of genes related to β-oxidation and a decrease in lipogenesis in DKO mice. High-fat diet administration in DKO significantly improved its life span. Lack of vitamin D signaling increases mortality in a model of overactivation of the IR by impairing lipid metabolism. Clinically, these results reveal the importance of adequate Vitamin D levels in T1D patients.
- Published
- 2022
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35. Endometrial PTEN Deficiency Leads to SMAD2/3 Nuclear Translocation.
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Eritja N, Navaridas R, Ruiz-Mitjana A, Vidal-Sabanés M, Egea J, Encinas M, Matias-Guiu X, and Dolcet X
- Abstract
TGF-β has a dichotomous function, acting as tumor suppressor in premalignant cells but as a tumor promoter for cancerous cells. These contradictory functions of TGF-β are caused by different cellular contexts, including both intracellular and environmental determinants. The TGF-β/SMAD and the PI3K/PTEN/AKT signal transduction pathways have an important role in the regulation of epithelial cell homeostasis and perturbations in either of these two pathways' contributions to endometrial carcinogenesis. We have previously demonstrated that both PTEN and SMAD2/3 display tumor-suppressive functions in the endometrium, and genetic ablation of either gene results in sustained activation of PI3K/AKT signaling that suppresses TGF-β-induced apoptosis and enhances cell proliferation of mouse endometrial cells. However, the molecular and cellular effects of PTEN deficiency on TGF-β/SMAD2/3 signaling remain controversial. Here, using an in vitro and in vivo model of endometrial carcinogenesis, we have demonstrated that loss of PTEN leads to a constitutive SMAD2/3 nuclear translocation. To ascertain the function of nuclear SMAD2/3 downstream of PTEN deficiency, we analyzed the effects of double deletion PTEN and SMAD2/3 in mouse endometrial organoids. Double PTEN/SMAD2/3 ablation results in a further increase of cell proliferation and enlarged endometrial organoids compared to those harboring single PTEN, suggesting that nuclear translocation of SMAD2/3 constrains tumorigenesis induced by PTEN deficiency.
- Published
- 2021
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36. ENDOG Impacts on Tumor Cell Proliferation and Tumor Prognosis in the Context of PI3K/PTEN Pathway Status.
- Author
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Barés G, Beà A, Hernández L, Navaridas R, Felip I, Megino C, Blasco N, Nadeu F, Campo E, Llovera M, Dolcet X, and Sanchis D
- Abstract
EndoG influences mitochondrial DNA replication and is involved in somatic cell proliferation. Here, we investigated the effect of ENDOG/Endog expression on proliferation in different tumor models. Noteworthy, ENDOG deficiency reduced proliferation of endometrial tumor cells expressing low PTEN/high p -AKT levels, and Endog deletion blunted the growth of PTEN-deficient 3D endometrial cultures. Furthermore, ENDOG silencing reduced proliferation of follicular thyroid carcinoma and glioblastoma cell lines with high p -AKT expression. High ENDOG expression was associated with a short time to treatment in a cohort of patients with chronic lymphocytic leukemia (CLL), a B-cell lymphoid neoplasm with activation of PI3K/AKT. This clinical impact was observed in the less aggressive CLL subtype with mutated IGHV in which high ENDOG and low PTEN levels were associated with worse outcome. In summary, our results show that reducing ENDOG expression hinders growth of some tumors characterized by low PTEN activity and high p -AKT expression and that ENDOG has prognostic value for some cancer types.
- Published
- 2021
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37. Involvement of the mitochondrial nuclease EndoG in the regulation of cell proliferation through the control of reactive oxygen species.
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Blasco N, Beà A, Barés G, Girón C, Navaridas R, Irazoki A, López-Lluch G, Zorzano A, Dolcet X, Llovera M, and Sanchis D
- Subjects
- Animals, Cell Cycle, Glycogen Synthase Kinase 3 beta, HEK293 Cells, Humans, Mice, Rats, Apoptosis, Cell Proliferation, Endodeoxyribonucleases, Mitochondria, Reactive Oxygen Species
- Abstract
The apoptotic nuclease EndoG is involved in mitochondrial DNA replication. Previous results suggested that, in addition to regulate cardiomyocyte hypertrophy, EndoG could be involved in cell proliferation. Here, by using in vivo and cell culture models, we investigated the role of EndoG in cell proliferation. Genetic deletion of Endog both in vivo and in cultured cells or Endog silencing in vitro induced a defect in rodent and human cell proliferation with a tendency of cells to accumulate in the G
1 phase of cell cycle and increased reactive oxygen species (ROS) production. The defect in cell proliferation occurred with a decrease in the activity of the AKT/PKB-GSK-3β-Cyclin D axis and was reversed by addition of ROS scavengers. EndoG deficiency did not affect the expression of ROS detoxifying enzymes, nor the expression of the electron transport chain complexes and oxygen consumption rate. Addition of the micropeptide Humanin to EndoG-deficient cells restored AKT phosphorylation and proliferation without lowering ROS levels. Thus, our results show that EndoG is important for cell proliferation through the control of ROS and that Humanin can restore cell division in EndoG-deficient cells and counteracts the effects of ROS on AKT phosphorylation., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2020
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38. T-Type Calcium Channels as Potential Therapeutic Targets in Vemurafenib-Resistant BRAF V600E Melanoma.
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Barceló C, Sisó P, Maiques O, García-Mulero S, Sanz-Pamplona R, Navaridas R, Megino C, Felip I, Urdanibia I, Eritja N, Soria X, Piulats JM, Penin RM, Dolcet X, Matías-Guiu X, Martí RM, and Macià A
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Calcium Channel Blockers therapeutic use, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Humans, Melanoma genetics, Melanoma pathology, Mice, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms genetics, Skin Neoplasms pathology, Vemurafenib pharmacology, Vemurafenib therapeutic use, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Calcium Channel Blockers pharmacology, Calcium Channels, T-Type metabolism, Melanoma drug therapy, Protein Kinase Inhibitors pharmacology, Skin Neoplasms drug therapy
- Abstract
Melanoma is a malignant neoplasia that is highly resistant to chemotherapy and radiotherapy and is associated with poor prognosis in advanced stage. Targeting melanoma that harbors the common BRAF
V600E mutation with kinase inhibitors, such as vemurafenib, reduces tumor burden, but these tumors frequently acquire resistance to these drugs. We previously proposed that T-type calcium channel (TTCC) expression may serve as a biomarker for melanoma progression and prognosis, and we showed that TTCC blockers reduce migration and invasion rates because of autophagy blockade only in BRAFV600E -mutant melanoma cells. Here, we demonstrated that high expression of the TTCC Cav3.1 isoform is related to autophagic status in vemurafenib-resistant BRAFV600E -mutant melanoma cells and human biopsies, and in silico analysis revealed an enrichment of Cav3.1 expression in post-treatment melanomas. We also demonstrated that the TTCC blocker mibefradil induces apoptosis and impairs migration and invasion via inhibition of autophagy in resistant melanoma cells and mouse xenograft models. Moreover, we identified an association between PTEN status and Cav3.1 expression in these cells as a marker of sensitivity to combination therapy in resistant cells. Together, our results suggest that TTCC blockers offer a potential targeted therapy in resistant BRAFV600E -mutant melanoma and a therapeutic strategy to reduce progression toward BRAF inhibitor resistance., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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39. Cytoplasmic cyclin D1 regulates glioblastoma dissemination.
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Cemeli T, Guasch-Vallés M, Nàger M, Felip I, Cambray S, Santacana M, Gatius S, Pedraza N, Dolcet X, Ferrezuelo F, Schuhmacher AJ, Herreros J, and Garí E
- Subjects
- Animals, Biomarkers, Tumor metabolism, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Line, Tumor, Cell Movement, Cyclin D1 metabolism, Cytoplasm metabolism, Glioblastoma metabolism, Glioblastoma pathology, Humans, Male, Mice, Mice, SCID, Neoplasm Invasiveness, Biomarkers, Tumor genetics, Brain Neoplasms genetics, Cyclin D1 genetics, Gene Expression Regulation, Neoplastic, Glioblastoma genetics
- Abstract
Glioblastoma (GBM) is a highly invasive brain neoplasia with an elevated recurrence rate after surgical resection. The cyclin D1 (Ccnd1)/Cdk4-retinoblastoma 1 (RB1) axis is frequently altered in GBM, leading to overproliferation by RB1 deletion or by Ccnd1-Cdk4 overactivation. High levels of Ccnd1-Cdk4 also promote GBM cell invasion by mechanisms that are not so well understood. The purpose of this work is to elucidate the in vivo role of cytoplasmic Ccnd1-Cdk4 activity in the dissemination of GBM. We show that Ccnd1 activates the invasion of primary human GBM cells through cytoplasmic RB1-independent mechanisms. By using GBM mouse models, we observed that evaded GBM cells showed cytoplasmic Ccnd1 colocalizing with regulators of cell invasion such as RalA and paxillin. Our genetic data strongly suggest that, in GBM cells, the Ccnd1-Cdk4 complex is acting upstream of those regulators. Accordingly, expression of Ccnd1 induces focal adhesion kinase, RalA and Rac1 activities. Finally, in vivo experiments demonstrated increased GBM dissemination after expression of membrane-targeted Ccnd1. We conclude that Ccnd1-Cdk4 activity promotes GBM dissemination through cytoplasmic and RB1-independent mechanisms. Therefore, inhibition of Ccnd1-Cdk4 activity may be useful to hinder the dissemination of recurrent GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2019
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40. Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer.
- Author
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Felip I, Moiola CP, Megino-Luque C, Lopez-Gil C, Cabrera S, Solé-Sánchez S, Muñoz-Guardiola P, Megias-Roda E, Pérez-Montoyo H, Alfon J, Yeste-Velasco M, Santacana M, Dolcet X, Reques A, Oaknin A, Rodríguez-Freixinos V, Lizcano JM, Domènech C, Gil-Moreno A, Matias-Guiu X, Colas E, and Eritja N
- Subjects
- Aged, Animals, Autophagy drug effects, Cell Cycle Proteins biosynthesis, Cell Cycle Proteins genetics, Cell Line, Tumor, Cell Proliferation drug effects, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Endometrial Neoplasms metabolism, Endometrial Neoplasms pathology, Female, Humans, Mice, Middle Aged, Protein Serine-Threonine Kinases biosynthesis, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Repressor Proteins biosynthesis, Repressor Proteins genetics, Up-Regulation drug effects, Antineoplastic Agents pharmacology, Cell Cycle Proteins metabolism, Endometrial Neoplasms drug therapy, Protein Serine-Threonine Kinases antagonists & inhibitors, Repressor Proteins metabolism, Small Molecule Libraries pharmacology
- Abstract
Objectives: The PI3K/AKT/mTOR pathway is frequently overactivated in endometrial cancer (EC). We assessed the efficacy of ABTL0812, a novel first-in-class molecule presenting a unique mechanism of action inhibiting this pathway., Methods: We investigated the effects of ABTL0812 on proliferation, cell death and modulation of intracellular signaling pathways in a wide panel of endometrioid and non-endometrioid cell lines, an inducible PTEN knock-out murine model, and two patient-derived xenograft murine models of EC. Then, TRIB3 expression was evaluated as potential ABTL0812 pharmacodynamic biomarker in a Phase 1b/2a clinical trial., Results: ABTL0812 induced an upregulation of TRIB3 expression, resulting in the PI3K/AKT/mTOR axis inhibition and autophagy cell death induction on EC cells but not in healthy endometrial cells. ABTL0812 treatment also impaired PTEN knock-out cells to progress from hyperplasia to cancer. The therapeutic effects of ABTL0812 were demonstrated in vivo. ABTL0812 increased TRIB3 mRNA levels in whole blood samples of eight EC patients, demonstrating that TRIB3 mRNA could be used as a pharmacodynamic biomarker to monitor the ABTL0812 treatment., Conclusions: ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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41. Tumor suppressive function of E2F-1 on PTEN-induced serrated colorectal carcinogenesis.
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Dosil MA, Navaridas R, Mirantes C, Tarragona J, Eritja N, Felip I, Urdanibia I, Megino C, Domingo M, Santacana M, Gatius S, Piñol C, Barceló C, Maiques O, Macià A, Velasco A, Vaquero M, Matias-Guiu X, and Dolcet X
- Subjects
- Animals, Apoptosis, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, DNA Damage, E2F1 Transcription Factor genetics, Gene Expression Regulation, Neoplastic, HT29 Cells, Humans, Mice, Knockout, Mitogen-Activated Protein Kinases metabolism, PTEN Phosphohydrolase genetics, Signal Transduction, Tumor Suppressor Proteins genetics, ras Proteins metabolism, Carcinogenesis, Colorectal Neoplasms enzymology, E2F1 Transcription Factor metabolism, PTEN Phosphohydrolase metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Many human cancers present Phosphatase and tensin homolog (PTEN) deficiency and between 20 and 30% of colorectal tumors show PTEN loss. The transcription factor, E2 promoter binding factor 1 (E2F-1), exhibits tumor promoter or suppressive functions depending on cellular type and tissue context, but its role in the progression and development of colorectal carcinogenesis was largely unknown. Here, using a tamoxifen-inducible PTEN knockout mouse model, we have demonstrated that loss of PTEN leads to the development of colorectal tumorigenesis through the serrated pathway. Next, we studied PTEN loss-driven colorectal lesions in the context of E2F-1 deficiency in vivo. Our results revealed that monoallelic and biallelic absence of E2F-1 led to an increased incidence and progression of serrated tumorigenesis induced by PTEN loss. Finally, we investigated the mechanisms by which double PTEN/E2F-1 deficiency leads to enhanced tumorigenesis. We found that colorectal tumors from PTEN/E2F-1 double knockout mice and the human colorectal carcinoma cell line HT29 with shRNA-mediated downregulation of PTEN and E2F-1 exhibit hyperactivation of the RAS-MAPK pathway, accumulation of DNA damage and resistance to apoptosis. To date, this is the first preclinical study evaluating the effect of genetic deletion of E2F-1 in colorectal malignancies driven by PTEN deficiency. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2019
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42. A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-β in mouse endometrium.
- Author
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Eritja N, Felip I, Dosil MA, Vigezzi L, Mirantes C, Yeramian A, Navaridas R, Santacana M, Llobet-Navas D, Yoshimura A, Nomura M, Encinas M, Matias-Guiu X, and Dolcet X
- Subjects
- Animals, Apoptosis drug effects, Apoptosis genetics, Cell Proliferation drug effects, Cell Proliferation genetics, Endometrium cytology, Endometrium metabolism, Epithelial Cells cytology, Epithelial Cells metabolism, Feedback, Physiological, Female, Gene Expression Regulation, Mice, Mice, Knockout, PTEN Phosphohydrolase antagonists & inhibitors, PTEN Phosphohydrolase deficiency, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Smad3 Protein antagonists & inhibitors, Smad3 Protein deficiency, Transcription, Genetic, Transforming Growth Factor beta genetics, Transforming Growth Factor beta metabolism, Endometrium drug effects, Epithelial Cells drug effects, PTEN Phosphohydrolase genetics, Smad3 Protein genetics, Transforming Growth Factor beta pharmacology
- Abstract
The TGF-β/Smad and the PI3K/AKT signaling pathways are important regulators of proliferation and apoptosis, and their alterations lead to cancer development. TGF-β acts as a tumor suppressor in premalignant cells, but it is a tumor promoter for cancerous cells. Such dichotomous actions are dictated by different cellular contexts. Here, we have unveiled a PTEN-Smad3 regulatory loop that provides a new insight in the complex cross talk between TGF-β/Smad and PI3K/AKT signaling pathways. We demonstrate that TGF-β triggers apoptosis of wild-type polarized endometrial epithelial cells by a Smad3-dependent activation of PTEN transcription, which results in the inhibition of PI3K/AKT signaling pathway. We show that specific Smad3 knockdown or knockout reduces basal and TGF-β-induced PTEN expression in endometrial cells, resulting in a blockade of TGF-β-induced apoptosis and an enhancement of cell proliferation. Likewise Smad3 deletion, PTEN knockout prevents TGF-β-induced apoptosis and increases cell proliferation by increasing PI3K/AKT/mTOR signaling. In summary, our results demonstrate that Smad3-PTEN signaling axis determine cellular responses to TGF-β.
- Published
- 2017
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43. Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias.
- Author
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Dosil MA, Mirantes C, Eritja N, Felip I, Navaridas R, Gatius S, Santacana M, Colàs E, Moiola C, Schoenenberger JA, Encinas M, Garí E, Matias-Guiu X, and Dolcet X
- Subjects
- Animals, Carcinogenesis, Cyclin D1 antagonists & inhibitors, Cyclin D1 metabolism, Cyclin-Dependent Kinase 4 antagonists & inhibitors, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase 6 antagonists & inhibitors, Cyclin-Dependent Kinase 6 genetics, Disease Models, Animal, Endometrial Neoplasms genetics, Endometrial Neoplasms pathology, Female, Humans, Mice, Mice, Knockout, Tamoxifen adverse effects, Transplantation, Heterologous, Antineoplastic Agents pharmacology, Cyclin D1 genetics, Endometrial Neoplasms drug therapy, PTEN Phosphohydrolase genetics, Piperazines pharmacology, Protein Kinase Inhibitors pharmacology, Pyridines pharmacology
- Abstract
PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD-332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen-inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten-deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D-CDK4/6 activity in their development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2017
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- View/download PDF
44. Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer.
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Eritja N, Chen BJ, Rodríguez-Barrueco R, Santacana M, Gatius S, Vidal A, Martí MD, Ponce J, Bergadà L, Yeramian A, Encinas M, Ribera J, Reventós J, Boyd J, Villanueva A, Matias-Guiu X, Dolcet X, and Llobet-Navàs D
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor, Disease Progression, Endometrial Neoplasms enzymology, Endometrial Neoplasms ultrastructure, Endoplasmic Reticulum Stress drug effects, Enzyme Activation drug effects, Female, Humans, Mice, Nude, Mitogen-Activated Protein Kinases metabolism, Niacinamide analogs & derivatives, Niacinamide pharmacology, Niacinamide therapeutic use, Phenylurea Compounds pharmacology, Phenylurea Compounds therapeutic use, Sorafenib, Xenograft Model Antitumor Assays, Autophagy drug effects, Endometrial Neoplasms drug therapy, Endometrial Neoplasms pathology, Molecular Targeted Therapy
- Abstract
Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.
- Published
- 2017
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45. Endometrial Carcinoma: Specific Targeted Pathways.
- Author
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Eritja N, Yeramian A, Chen BJ, Llobet-Navas D, Ortega E, Colas E, Abal M, Dolcet X, Reventos J, and Matias-Guiu X
- Subjects
- Endometrial Neoplasms metabolism, Female, Humans, Molecular Targeted Therapy trends, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, TOR Serine-Threonine Kinases metabolism, Transforming Growth Factor beta metabolism, beta Catenin metabolism, Antineoplastic Agents therapeutic use, Endometrial Neoplasms drug therapy, Molecular Targeted Therapy methods, Signal Transduction drug effects
- Abstract
Endometrial cancer (EC) is the most common gynecologic malignancy in the western world with more than 280,000 cases per year worldwide. Prognosis for EC at early stages, when primary surgical resection is the most common initial treatment, is excellent. Five-year survival rate is around 70 %.Several molecular alterations have been described in the different types of EC. They occur in genes involved in important signaling pathways. In this chapter, we will review the most relevant altered pathways in EC, including PI3K/AKT/mTOR, RAS-RAF-MEK-ERK, Tyrosine kinase, WNT/β-Catenin, cell cycle, and TGF-β signaling pathways. At the end of the chapter, the most significant clinical trials will be briefly discussed.This information is important to identify specific targets for therapy.
- Published
- 2017
- Full Text
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46. Bioluminescence Imaging to Monitor the Effects of the Hsp90 Inhibitor NVP-AUY922 on NF-κB Pathway in Endometrial Cancer.
- Author
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Yeramian A, García V, Bergadà L, Domingo M, Santacana M, Valls J, Martinez-Alonso M, Carceller JA, Cussac AL, Dolcet X, and Matias-Guiu X
- Subjects
- Animals, Apoptosis drug effects, Cell Cycle Checkpoints drug effects, Cell Hypoxia drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Clone Cells, Endometrial Neoplasms pathology, Female, HSP70 Heat-Shock Proteins metabolism, HSP90 Heat-Shock Proteins metabolism, Humans, Luciferases metabolism, Mice, Xenograft Model Antitumor Assays, Diagnostic Imaging methods, Endometrial Neoplasms diagnosis, HSP90 Heat-Shock Proteins antagonists & inhibitors, Isoxazoles pharmacology, Luminescent Measurements methods, NF-kappa B metabolism, Resorcinols pharmacology, Signal Transduction drug effects
- Abstract
Purpose: In this study, we first aimed to evaluate the effects in vitro and in vivo, of the Hsp90 inhibitor NVP-AUY922, in endometrial cancer (EC). We also aimed to track nuclear factor kappa B (NF-κB) signalling, a key pathway involved in endometrial carcinogenesis and to check whether NVP-AUY922 treatment modulates it both in vitro and in vivo., Procedures: I n vitro effects of NVP-AUY922 on EC cell growth and the signalling pathways were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic assays, Western Blot and luciferase assay. NVP-AUY922 effect on Ishikawa (IK) xenograft growth was evaluated in vivo, and NF-κB activity was monitored using bioluminescence imaging., Results: NVP-AUY922 inhibited the growth of three endometrial cell lines tested in vitro. In vivo, NVP-AUY922 reduced tumour growth of 47 % (p = 0.042) compared to control condition. Moreover, the bioluminescence signal of the tumours harbouring IK NF-κB-LUC cells was significantly reduced in NVP-AUY922-treated animals compared to untreated ones., Conclusions: NVP-AUY922 reduced EC tumour growth and NF-κB signalling both in vitro and in vivo. As therapeutic resistance of EC remains a challenge for oncologists nowadays, we think that NVP-AUY922 represents a valid alternative to conventional chemotherapy, and we believe that this approach for assessing and tracking the activation of NF-κB pathway may be of therapeutic benefit.
- Published
- 2016
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47. Effects of the multikinase inhibitors Sorafenib and Regorafenib in PTEN deficient neoplasias.
- Author
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Mirantes C, Dosil MA, Eritja N, Felip I, Gatius S, Santacana M, Matias-Guiu X, and Dolcet X
- Subjects
- Animals, Antineoplastic Agents pharmacology, Cell Line, Tumor drug effects, Disease Models, Animal, Female, Humans, Male, Niacinamide pharmacology, Niacinamide therapeutic use, PTEN Phosphohydrolase deficiency, Phenylurea Compounds pharmacology, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, Pyridines pharmacology, Sorafenib, Antineoplastic Agents therapeutic use, Carcinoma drug therapy, Endometrial Neoplasms drug therapy, Niacinamide analogs & derivatives, Phenylurea Compounds therapeutic use, Prostatic Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Pyridines therapeutic use, Thyroid Neoplasms drug therapy
- Abstract
The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) axis is frequently dysregulated in cancer due to mutations in different nodes of the pathway or constitutive activation of receptor tyrosine kinases. Multikinase inhibitors as sorafenib and regorafenib represent a therapeutic approach for the treatment of these types of tumours. In the present study, we have evaluated the anti-tumoural effects of Sorafenib and Regorafenib on endometrial, prostate and thyroid neoplasias. Both inhibitors reduced cell viability in vitro and lead to a disruption of the PI3K/AKT/mTOR pathway. In vivo, we have demonstrated that Sorafenib and Regorafenib reduce thyroid hyperplasias induced by the loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), although none of the treatments eliminated the disease. Altogether, we present the first study that correlates the response to multikinase inhibitors with a specific mutation. Moreover, this is the first report characterising the response to Regorafenib in thyroid, prostate and endometrial neoplasias., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
- Full Text
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48. Biological Effects of Temsirolimus on the mTOR Pathway in Endometrial Carcinoma: A Pharmacodynamic Phase II Study.
- Author
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Santacana M, Coronado P, Matias-Guiu X, Romero I, Casado A, Gil-Moreno A, Dosil MA, Mota A, Moreno-Bueno G, Dolcet X, Llombart-Cussac A, and Poveda A
- Abstract
Objective: The PI3K/AKT/mTOR pathway is frequently aberrantly activated in endometrial carcinoma (EC). Temsirolimus is an mTOR inhibitor that has shown clinical activity in EC. We aimed to characterize the biological effects on mTOR pathway of temsirolimus in treatment-naive patients with primary EC, and to identify potential biomarkers associated with a short-term exposure to temsirolimus., Materials and Methods: Patients with EC were treated with 4 doses of temsirolimus previous to surgery. The primary objective was the analysis of paired endometrial aspirates and posttreatment (hysterectomy specimens) tumor tissue samples for mTOR downstream effectors p-S6K1 and p-4BEP1 levels by immunohistochemistry. Secondary objectives included analysis of expression of other mTOR-related biomarkers by immunohistochemistry, as well as analysis of the predictive value of mutations in mTOR-related genes. Toxicity was also assessed., Results: Eleven patients were included in the study. p-S6K1 expression was reduced after treatment with temsirolimus in all patients. Variations of the expression of other mTOR-related proteins including p-4BEP1, PTEN, p-AKT, p53, p27, BAD, Bcl-2, Ki67, and cyclin D1 were also observed. Interestingly, the biological effects of the drug were more evident 1 week after the last dose of temsirolimus. Effects were less evident on tumors harboring mutations in NRAS. Toxicity was acceptable, being mucositis the most frequent adverse event., Conclusions: Short temsirolimus exposure effectively inhibits mTOR pathway in patients with endometrial cancer. p-S6K1 expression is a promising biomarker of sensitivity. The preoperative window opportunity in EC is a realistic scenario for biological knowledge and target development.
- Published
- 2016
- Full Text
- View/download PDF
49. Cytoplasmic cyclin D1 regulates cell invasion and metastasis through the phosphorylation of paxillin.
- Author
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Fusté NP, Fernández-Hernández R, Cemeli T, Mirantes C, Pedraza N, Rafel M, Torres-Rosell J, Colomina N, Ferrezuelo F, Dolcet X, and Garí E
- Subjects
- Animals, Cell Line, Tumor, Cell Membrane metabolism, Cyclin D1 deficiency, Cyclin-Dependent Kinase 4 metabolism, Down-Regulation genetics, Fibroblasts metabolism, Gene Knockdown Techniques, HEK293 Cells, Humans, Mice, Neoplasm Invasiveness, Neoplasm Metastasis, Phosphorylation, Phosphoserine metabolism, Protein Binding, Rats, Substrate Specificity, rac1 GTP-Binding Protein metabolism, Cyclin D1 metabolism, Cytoplasm metabolism, Neoplasms metabolism, Neoplasms pathology, Paxillin metabolism
- Abstract
Cyclin D1 (Ccnd1) together with its binding partner Cdk4 act as a transcriptional regulator to control cell proliferation and migration, and abnormal Ccnd1·Cdk4 expression promotes tumour growth and metastasis. While different nuclear Ccnd1·Cdk4 targets participating in cell proliferation and tissue development have been identified, little is known about how Ccnd1·Cdk4 controls cell adherence and invasion. Here, we show that the focal adhesion component paxillin is a cytoplasmic substrate of Ccnd1·Cdk4. This complex phosphorylates a fraction of paxillin specifically associated to the cell membrane, and promotes Rac1 activation, thereby triggering membrane ruffling and cell invasion in both normal fibroblasts and tumour cells. Our results demonstrate that localization of Ccnd1·Cdk4 to the cytoplasm does not simply act to restrain cell proliferation, but constitutes a functionally relevant mechanism operating under normal and pathological conditions to control cell adhesion, migration and metastasis through activation of a Ccnd1·Cdk4-paxillin-Rac1 axis.
- Published
- 2016
- Full Text
- View/download PDF
50. Characterization of cytoplasmic cyclin D1 as a marker of invasiveness in cancer.
- Author
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Fusté NP, Castelblanco E, Felip I, Santacana M, Fernández-Hernández R, Gatius S, Pedraza N, Pallarés J, Cemeli T, Valls J, Tarres M, Ferrezuelo F, Dolcet X, Matias-Guiu X, and Garí E
- Subjects
- Amino Acid Motifs genetics, Animals, Biomarkers, Tumor genetics, Breast Neoplasms metabolism, Cell Line, Tumor, Cell Membrane metabolism, Cells, Cultured, Colonic Neoplasms metabolism, Cyclin D1 genetics, Endometrial Neoplasms metabolism, Female, Humans, Immunohistochemistry, Male, Mice, Nude, Mice, SCID, Microscopy, Confocal, Neoplasm Invasiveness, Prostatic Neoplasms metabolism, Biomarkers, Tumor metabolism, Cyclin D1 metabolism, Cytoplasm metabolism, Neoplasms metabolism
- Abstract
Cyclin D1 (Ccnd1) is a proto-oncogen amplified in many different cancers and nuclear accumulation of Ccnd1 is a characteristic of tumor cells. Ccnd1 activates the transcription of a large set of genes involved in cell cycle progress and proliferation. However, Ccnd1 also targets cytoplasmic proteins involved in the regulation of cell migration and invasion. In this work, we have analyzed by immunohistochemistry the localization of Ccnd1 in endometrial, breast, prostate and colon carcinomas with different types of invasion. The number of cells displaying membranous or cytoplasmic Ccnd1 was significantly higher in peripheral cells than in inner cells in both collective and pushing invasion patterns of endometrial carcinoma, and in collective invasion pattern of colon carcinoma. Also, the cytoplasmic localization of Ccnd1 was higher when tumors infiltrated as single cells, budding or small clusters of cells. To evaluate cytoplasmic function of cyclin D1, we have built a variant (Ccnd1-CAAX) that remains attached to the cell membrane therefore sequestering this cyclin in the cytoplasm. Tumor cells harboring Ccnd1-CAAX showed high levels of invasiveness and metastatic potential compared to those containing the wild type allele of Ccnd1. However, Ccnd1-CAAX expression did not alter proliferative rates of tumor cells. We hypothesize that the role of Ccnd1 in the cytoplasm is mainly associated with the invasive capability of tumor cells. Moreover, we propose that subcellular localization of Ccnd1 is an interesting guideline to measure cancer outcome., Competing Interests: The authors declare that they have no conflict of Interest.
- Published
- 2016
- Full Text
- View/download PDF
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