34 results on '"Desideri, Marianna"'
Search Results
2. microRNA-378a-5p iS a novel positive regulator of melanoma progression
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Tupone, Maria Grazia, D’Aguanno, Simona, Di Martile, Marta, Valentini, Elisabetta, Desideri, Marianna, Trisciuoglio, Daniela, Donzelli, Sara, Sacconi, Andrea, Buglioni, Simonetta, Ercolani, Cristiana, Biagioni, Alessio, Fibbi, Gabriella, Fattore, Luigi, Mancini, Rita, Ciliberto, Gennaro, Blandino, Giovanni, and Del Bufalo, Donatella
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- 2020
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3. Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb
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D’Aguanno, Simona, Valentini, Elisabetta, Tupone, Maria Grazia, Desideri, Marianna, Di Martile, Marta, Spagnuolo, Manuela, Buglioni, Simonetta, Ercolani, Cristiana, Falcone, Italia, De Dominici, Marco, Milella, Michele, Rizzo, Maria Giulia, Calabretta, Bruno, Cota, Carlo, Anichini, Andrea, Trisciuoglio, Daniela, and Del Bufalo, Donatella
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- 2018
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4. VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2-dependent Ca²⁺ signaling
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Favia, Annarita, Desideri, Marianna, Gambara, Guido, D'Alessio, Alessio, Ruas, Margarida, Esposito, Bianca, Del Bufalo, Donatella, Parrington, John, Ziparo, Elio, Palombi, Fioretta, Galione, Antony, and Filippini, Antonio
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- 2014
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5. Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma
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Di Martile, Marta, Desideri, Marianna, Tupone, Maria Grazia, Buglioni, Simonetta, Antoniani, Barbara, Mastroiorio, Carlotta, Falcioni, Rita, Ferraresi, Virginia, Baldini, Nicola, Biagini, Roberto, Milella, Michele, Trisciuoglio, Daniela, and Del Bufalo, Donatella
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- 2018
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6. BCL-XL overexpression promotes tumor progression-associated properties
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Trisciuoglio, Daniela, Tupone, Maria Grazia, Desideri, Marianna, Di Martile, Marta, Gabellini, Chiara, Buglioni, Simonetta, Pallocca, Matteo, Alessandrini, Gabriele, D’Aguanno, Simona, and Del Bufalo, Donatella
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- 2017
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7. Removal of the BH4 Domain from Bcl-2 Protein Triggers an Autophagic Process that Impairs Tumor Growth
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Trisciuoglio, Daniela, De Luca, Teresa, Desideri, Marianna, Passeri, Daniela, Gabellini, Chiara, Scarpino, Stefania, Liang, Chengyu, Orlandi, Augusto, and Del Bufalo, Donatella
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- 2013
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8. TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo
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Gambara, Guido, Desideri, Marianna, Stoppacciaro, Antonella, Padula, Fabrizio, De Cesaris, Paola, Starace, Donatella, Tubaro, Andrea, del Bufalo, Donatella, Filippini, Antonio, Ziparo, Elio, and Riccioli, Anna
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- 2015
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9. The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms
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Ciuffreda, Ludovica, Di Sanza, Cristina, Cesta Incani, Ursula, Eramo, Adriana, Desideri, Marianna, Biagioni, Francesca, Passeri, Daniela, Falcone, Italia, Sette, Giovanni, Bergamo, Paola, Anichini, Andrea, Sabapathy, Kanaga, McCubrey, James A., Ricciardi, Maria Rosaria, Tafuri, Agostino, Blandino, Giovanni, Orlandi, Augusto, De Maria, Ruggero, Cognetti, Francesco, Del Bufalo, Donatella, and Milella, Michele
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- 2012
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10. BH4 domain of bcl-2 protein is required for its proangiogenic function under hypoxic condition
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Gabellini, Chiara, De Luca, Teresa, Trisciuoglio, Daniela, Desideri, Marianna, Di Martile, Marta, Passeri, Daniela, Candiloro, Antonio, Biffoni, Mauro, Rizzo, Maria Giulia, Orlandi, Augusto, and Del Bufalo, Donatella
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- 2013
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11. Down-regulation of the PTTG1 proto-oncogene contributes to the melanoma suppressive effects of the cyclin-dependent kinase inhibitor PHA-848125
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Caporali, Simona, Alvino, Ester, Levati, Lauretta, Esposito, Alessia I., Ciomei, Marina, Brasca, Maria G., Del Bufalo, Donatella, Desideri, Marianna, Bonmassar, Enzo, Pfeffer, Ulrich, and DʼAtri, Stefania
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- 2012
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12. Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma
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Fianco, Giulia, Mongiardi, Maria Patrizia, Levi, Andrea, Luca, Teresa De, Desideri, Marianna, Trisciuoglio, Daniela, Bufalo, Donatella Del, Cinà, Irene, Benedetto, Anna Di, Mottolese, Marcella, Gentile, Antonietta, Centonze, Diego, Ferrè, Fabrizio, Barilà, Daniela, Fianco, Giulia, Mongiardi, Maria Patrizia, Levi, Andrea, Luca, Teresa De, Desideri, Marianna, Trisciuoglio, Daniela, Bufalo, Donatella Del, Cinã , Irene, Benedetto, Anna Di, Mottolese, Marcella, Gentile, Antonietta, Centonze, Diego, Ferrè, Fabrizio, and Barilà , Daniela
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Vascular Endothelial Growth Factor A ,0301 basic medicine ,Angiogenesis ,Immunology and Microbiology (all) ,Neovascularization ,angiogenesis ,cell biology ,Biology (General) ,cancer biology ,Caspase 8 ,Neovascularization, Pathologic ,General Neuroscience ,NF-kappa B ,General Medicine ,Prognosis ,Vascular endothelial growth factor A ,cell death ,Cytokines ,Medicine ,Settore MED/26 - Neurologia ,medicine.symptom ,signal transduction ,medicine.drug ,QH301-705.5 ,Science ,Short Report ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,medicine ,Humans ,cancer ,Neoplastic transformation ,human ,mouse ,Temozolomide ,Neuroscience (all) ,Biochemistry, Genetics and Molecular Biology (all) ,General Immunology and Microbiology ,Microarray analysis techniques ,Gene Expression Profiling ,Cancer ,angiogenesi ,Microarray Analysis ,medicine.disease ,Gene expression profiling ,Settore BIO/18 - Genetica ,cell proliferation ,030104 developmental biology ,Drug Resistance, Neoplasm ,Immunology ,Cancer research ,Glioblastoma - Abstract
Caspase-8 is a key player in extrinsic apoptosis and its activity is often downregulated in cancer. However, human Caspase-8 expression is retained in some tumors, including glioblastoma (GBM), suggesting that it may support cancer growth in these contexts. GBM, the most aggressive of the gliomas, is characterized by extensive angiogenesis and by an inflammatory microenvironment that support its development and resistance to therapies. We have recently shown that Caspase-8 sustains neoplastic transformation in vitro in human GBM cell lines. Here, we demonstrate that Caspase-8, through activation of NF-kB, enhances the expression and secretion of VEGF, IL-6, IL-8, IL-1beta and MCP-1, leading to neovascularization and increased resistance to Temozolomide. Importantly, the bioinformatics analysis of microarray gene expression data derived from a set of high-grade human gliomas, shows that high Caspase-8 expression levels correlate with a worse prognosis. DOI: http://dx.doi.org/10.7554/eLife.22593.001, eLife digest Cancer cells are different to normal cells in various ways. Most cancer cells, for example, delete or switch off the gene for a protein called Caspase-8. This is because this protein is best known for promoting cell death and stopping tumor cells from growing. However, some cancers keep the gene for Caspase-8 switched on including glioblastoma, the most aggressive type of brain cancer in adults. This begged the question whether this protein may in fact promote the development of tumors under certain circumstances. Glioblastomas are often highly resistant to chemotherapy and can communicate with nearby cells using proteins called cytokines to promote the formation of new blood vessels. The new blood vessel allows the tumor to readily spread into healthy brain tissue, which in turn makes it difficult for surgeons to remove all the cancerous cells. As a result, glioblastomas almost always return after surgery, and so there is strong need for new effective treatments for this type of cancer. Fianco et al. have now investigated whether Caspase-8 helps glioblastomas to grow and form new blood vessels. One common method to study human cancer cells is to inject them into mice and watch how they grow, because these experiments mimic how tumors develop in the human body. When mice were injected with human glioblastoma cells with experimentally reduced levels of Caspase-8, the cells grew poorly and did not form as many new blood vessels as unaltered glioblastoma cells. Further experiments showed that, when grown in the laboratory, glioblastoma cells with less Caspase-8 were more sensitive to a chemotherapeutic drug called temozolomide. These findings confirm that Caspase-8 does boost the growth and drug resistance of at least one cancer. When Fianco et al. analyzed clinical data from patients affected by glioblastoma, they also observed that those patients with high levels of Caspase-8 often had the worse outcomes. Previous studies conducted in white blood cells showed that Caspase-8 activated a protein complex called NF-kB, which in turn led to the cells releasing cytokines. Fianco et al. have now verified that Caspase-8 promotes NF-kB activity also in glioblastoma cells, and that this causes the cancer cells to release more cytokines. As such, these findings reveal a clear link between Caspase-8 and the formation of new blood vessels by glioblastomas. Future studies are now needed to understand why Caspase-8 promotes cell death in some cancers but the formation of new blood vessels in others. Indeed, Caspase-8 might become a target for new anticancer drugs if it is possible to inhibit its cancer-boosting activity without interfering with its ability to promote cell death. DOI: http://dx.doi.org/10.7554/eLife.22593.002
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- 2017
13. BCL-XL overexpression promotes tumor progression-associated properties article
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Trisciuoglio, Daniela, Tupone, Maria Grazia, Desideri, Marianna, Di Martile, Marta, Gabellini, Chiara, Buglioni, Simonetta, Pallocca, Matteo, Alessandrini, Gabriele, D'Aguanno, Simona, and Del Bufalo, Donatella
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Cancer Research ,Skin Neoplasms ,Immunology ,Nude ,bcl-X Protein ,alpha Subunit ,Small Interfering ,Cell Line ,Cellular and Molecular Neuroscience ,Mice ,Cell Movement ,Animals ,Humans ,Melanoma ,Neovascularization ,Cell Proliferation ,Pathologic ,Neoplastic ,Tumor ,Cell Biology ,Brain Neoplasms ,Cell Line, Tumor ,Disease Progression ,Female ,Glioblastoma ,Hypoxia-Inducible Factor 1, alpha Subunit ,Mice, Nude ,Nanog Homeobox Protein ,Neoplastic Stem Cells ,Neovascularization, Pathologic ,Octamer Transcription Factor-3 ,RNA, Small Interfering ,SOXB1 Transcription Factors ,Signal Transduction ,Thiazolidines ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Gene Expression Regulation ,RNA ,Hypoxia-Inducible Factor 1 - Published
- 2017
14. Targeting of NAADP-dependent calcium signalling impairs growth and invasiveness of murine melanoma and tumor angiogenesis
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Favia, Annarita, Pafumi, Irene, Desideri, Marianna, Montesano, Camilla, Passeri, Daniela, Orlandi, Augusto, Del Bufalo, Donatella, Sergi, Manuel, Ziparo, Elio, Palombi, Fioretta, and Filippini, Antonio
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Tumor vascularization ,melanoma ,calcium signalling ,metastasis - Abstract
We have recently identified a novel transduction pathway through which Vascular Endothelial Growth Factor (VEGF) controls experimentally induced neoangiogenesis, specifically involving endothelial VEGF receptor subtype 2 and the release of intracellular calcium from NAADP (Nicotinic Acid Adenosine Dinucleotide Phosphate) responsive acidic stores (1). We have now extended this research to an in vivo model of tumor angiogenesis and show that the pharmacologic NAADP inhibitor Ned-19 (2) impairs the vascularization, growth and metastatic spreading of the very aggressive VEGF producing murine tumor, B16 melanoma. In parallel in vitro experiments, we tested whether Ned-19 could directly affect the production of VEGF by the tumor cells, and found that treatment of B16 cells with Ned-19 unexpectedly results in increased VEGF release. These observations indicate that in our model 1) tumor angiogenesis is impaired by Ned-19 even in the presence of increased exposure to VEGF and 2) that NAADP system is active also in B16 melanoma cells. On the basis of this second observation further possible direct effects of Ned-19 on melanoma cell aggressiveness such as growth and invasivity are presently investigated and preliminary results suggest that NAADP system inhibition could potentially represent a twofold therapeutic strategy, directly targeting both tumor angiogenesis and tumor cell growth., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015
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- 2015
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15. Kinetochore-microtubule interactions as a promising target in anti-cancer therapy
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Orticello, Michela, Totta, Pierangela, Fiore, Mario, Desideri, Marianna, Passeri, Daniela, Lenzi, Jessica, Rosa, Alessandro, Orlandi, Augusto, Donatella, Del, Bufalo, Francesca, and Degrassi
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- 2013
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16. miR-211 and MITF modulation by Bcl-2 protein in melanoma cells.
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De Luca, Teresa, Pelosi, Andrea, Trisciuoglio, Daniela, D'Aguanno, Simona, Desideri, Marianna, Farini, Valentina, Di Martile, Marta, Bellei, Barbara, Tupone, Maria Grazia, Candiloro, Antonio, Regazzo, Giulia, Rizzo, Maria Giulia, and Del Bufalo, Donatella
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- 2016
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17. Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer.
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Del Bufalo, Donatella, Desideri, Marianna, De Luca, Teresa, Di Martile, Marta, Gabellini, Chiara, Monica, Valentina, Busso, Simone, Eramo, Adriana, De Maria, Ruggero, Milella, Michele, and Trisciuoglio, Daniela
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PEMETREXED , *NON-small-cell lung carcinoma , *HISTONE deacetylase , *THYMIDYLATE synthase , *GENE silencing , *CANCER stem cells - Abstract
Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed, a multi-target folate antagonist, has demonstrated efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS) expression. Among many other potential targets, histone deacetylase inhibitors (HDACi) modulate TS expression, potentially sensitizing to the cytotoxic action of anti-cancer drugs that target the folate pathway, such as pemetrexed. Since high levels of TS have been linked to clinical resistance to pemetrexed in NSCLC, herein we investigated the molecular and functional effects of combined pemetrexed and ITF2357, a pan-HDACi currently in clinical trials as an anti-cancer agent. Results: In NSCLC cell lines, HDAC inhibition by ITF2357 induced histone and tubulin acetylation and downregulated TS expression at the mRNA and protein level. In combination experiments in vitro ITF2357 and pemetrexed demonstrated sequence-dependent synergistic growth-inhibitory effects, with the sequence pemetrexed followed by ITF2357 inducing a strikingly synergistic reduction in cell viability and induction of both apoptosis and autophagy in all cell line models tested, encompassing both adenocarcinoma and squamous cell carcinoma. Conversely, simultaneous administration of both drugs achieved frankly antagonistic effects, while the sequence of ITF2357 followed by pemetrexed had additive to slightly synergistic growth-inhibitory effects only in certain cell lines. Similarly, highly synergistic growth inhibition was also observed in patient-derived lung cancer stem cells (LCSC) exposed to pemetrexed followed by ITF2357. In terms of molecular mechanisms of interaction, the synergistic growth-inhibitory effects observed were only partially related to TS modulation by ITF2357, as genetic silencing of TS expression potentiated growth inhibition by either pemetrexed or ITF2357 and, to a lesser extent, by their sequential combination. Genetic and pharmacological approaches provided an interesting link between the autophagic and apoptotic pathways, and showed that sequential pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival. Conclusions: Overall, these data provide a strong rationale for the clinical development of sequential schedules employing pemetrexed followed by HDACi in NSCLC. [ABSTRACT FROM AUTHOR]
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- 2014
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18. Papillary Carcinoma of the Thyroid: High Expression of COX-2 and Low Expression of KAI-1/CD82 Are Associated with Increased Tumor Invasiveness.
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Scarpino, Stefania, Duranti, Enrico, Giglio, Simona, Di Napoli, Arianna, Galafate, Dino, Del Bufalo, Donatella, Desideri, Marianna, Socciarelli, Fabio, Stoppacciaro, Antonella, and Ruco, Luigi
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THYROIDITIS ,PAPILLARY carcinoma ,CANCER invasiveness ,HEPATOCYTE growth factor ,METASTASIS ,CELL migration ,LYMPH nodes - Abstract
Background: We have previously demonstrated that expression of COX-2 is upregulated by hepatocyte growth factor in thyroid papillary carcinoma (TPC) cells and is associated with increased invasiveness of tumor cells. COX-2 upregulation was associated with downregulation of KAI-1/CD82, a metastasis suppressor molecule that has been associated with the metastatic potential of several solid tumors. In the present study, we have investigated the possibility that downregulation of KAI-1/CD82 may contribute to the invasiveness of papillary carcinoma cells. Methods: Expression of KAI-1/CD82 and its relation to COX-2 levels were investigated in 6 primary cultures of TPC, in 2 tumor cell lines (TPC-1 and K1), and in 55 tumor samples of TPC. The biological role of KAI-1/CD82 in regulating tumor invasiveness was investigated in TPC cell lines and primary cultures transfected with a pCDNA3.1/Hygro.KAI-1; transfected cells were tested in functional studies of cell migration and invasiveness. Finally, the role of KAI-1/CD82 in influencing TPC metastasis was investigated in vivo using nu/nu mice injected with K1-transfected cells. Results: We provide evidence that COX-2 and KAI-1/CD82 are inversely regulated in TPC primary cultures and in TPC-1 tumor cells. In fact, inhibition of COX-2 with NS398 is associated with a 2-9-fold upregulation of KAI-1/CD82 RNA. Moreover, a possible relation between COX-2 and KAI-1/CD82 was confirmed by the presence of a statistically significant inverse correlation in the expression of the two genes in 55 tumor samples of TPC ( r=−0.513; p=0.001). In 36 of 55 cases, tumor areas contained lower levels of KAI-1/CD82 RNA as compared with the corresponding normal tissue. Low expression of KAI-1/CD82 RNA in the tumor area was associated with extrathyroid extension of the disease in 16 of 19 cases ( p<0.04) and with lymph node metastasis in 11 of 14 cases (not significant). KAI-1/CD82 re-expression in tumor cells was associated with a significant decrease in their migratory (50-76% reduction) and invasive (46-65% reduction) capacity, even after hepatocyte growth factor stimulation. Finally, nu/nu mice injected with KAI-1/CD82-transfected K1 TPC cells developed fewer and smaller metastasis as compared with mice injected with vector-transfected K1 cells ( p=0.016). Conclusion: Our findings raise the possibility that downregulation of KAI-1/CD82 in TPC cells is one of the molecular mechanisms regulating their invasive and metastatic potential. [ABSTRACT FROM AUTHOR]
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- 2013
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19. LMNA Knock-Down Affects Differentiation and Progression of Human Neuroblastoma Cells.
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Maresca, Giovanna, Natoli, Manuela, Nardella, Marta, Arisi, Ivan, Trisciuoglio, Daniela, Desideri, Marianna, Brandi, Rossella, D'aguanno, Simona, Nicotra, Maria Rita, D'onofrio, Mara, Urbani, Andrea, Natali, Pier Giorgio, Del Bufalo, Donatella, Felsani, Armando, D'agnano, Igea, and Jun Li
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NEUROBLASTOMA ,NERVOUS system cancer ,LAMINS ,TUMORS ,PEDIATRIC research ,GENES - Abstract
Background: Neuroblastoma (NB) is one of the most aggressive tumors that occur in childhood. Although genes, such as MYCN, have been shown to be involved in the aggressiveness of the disease, the identification of new biological markers is still desirable. The induction of differentiation is one of the strategies used in the treatment of neuroblastoma. A-type lamins are components of the nuclear lamina and are involved in differentiation. We studied the role of Lamin A/C in the differentiation and progression of neuroblastoma. Methodology/Principal Findings: Knock-down of Lamin A/C (LMNA-KD) in neuroblastoma cells blocked retinoic acid- induced differentiation, preventing neurites outgrowth and the expression of neural markers. The genome-wide gene- expression profile and the proteomic analysis of LMNA-KD cells confirmed the inhibition of differentiation and demonstrated an increase of aggressiveness-related genes and molecules resulting in augmented migration/invasion, and increasing the drug resistance of the cells. The more aggressive phenotype acquired by LMNA-KD cells was also maintained in vivo after injection into nude mice. A preliminary immunohistochemistry analysis of Lamin A/C expression in nine primary stages human NB indicated that this protein is poorly expressed in most of these cases. Conclusions/Significance: We demonstrated for the first time in neuroblastoma cells that Lamin A/C plays a central role in the differentiation, and that the loss of this protein gave rise to a more aggressive tumor phenotype. [ABSTRACT FROM AUTHOR]
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- 2012
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20. Bcl-2 Regulates HIF-1α Protein Stabilization in Hypoxic Melanoma Cells via the Molecular Chaperone HSP90.
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Trisciuoglio, Daniela, Gabellini, Chiara, Desideri, Marianna, Ziparo, Elio, Zupi, Gabriella, and Del Bufalo, Donatella
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TRANSCRIPTION factors ,MOLECULAR chaperones ,HYPOXEMIA ,NEOVASCULARIZATION ,METASTASIS ,MELANOMA ,GENE expression ,GENETIC transcription ,TUMOR growth ,GENETICS - Abstract
Background: Hypoxia-Inducible Factor 1 (HIF-1) is a transcription factor that is a critical mediator of the cellular response to hypoxia. Enhanced levels of HIF-1α, the oxygen-regulated subunit of HIF-1, is often associated with increased tumour angiogenesis, metastasis, therapeutic resistance and poor prognosis. It is in this context that we previously demonstrated that under hypoxia, bcl-2 protein promotes HIF-1/Vascular Endothelial Growth Factor (VEGF)-mediated tumour angiogenesis. Methodology/Principal Findings: By using human melanoma cell lines and their stable or transient derivative bcl-2 overexpressing cells, the current study identified HIF-1α protein stabilization as a key regulator for the induction of HIF-1 by bcl-2 under hypoxia. We also demonstrated that bcl-2-induced accumulation of HIF-1α protein during hypoxia was not due to an increased gene transcription or protein synthesis. In fact, it was related to a modulation of HIF-1α protein expression at a post-translational level, indeed its degradation rate was faster in the control lines than in bcl-2 transfectants. The bcl-2- induced HIF-1α stabilization in response to low oxygen tension conditions was achieved through the impairment of ubiquitin-dependent HIF-1α degradation involving the molecular chaperone HSP90, but it was not dependent on the prolyl hydroxylation of HIF-1α protein. We also showed that bcl-2, HIF-1α and HSP90 proteins form a tri-complex that may contribute to enhancing the stability of the HIF-1α protein in bcl-2 overexpressing clones under hypoxic conditions. Finally, by using genetic and pharmacological approaches we proved that HSP90 is involved in bcl-2-dependent stabilization of HIF-1α protein during hypoxia, and in particular the isoform HSP90b is the main player in this phenomenon. Conclusions/Significance: We identified the stabilization of HIF-1α protein as a mechanism through which bcl-2 induces the activation of HIF-1 in hypoxic tumour cells involving the β isoform of molecular chaperone HSP90. [ABSTRACT FROM AUTHOR]
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- 2010
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21. Bcl-2 overexpression in melanoma cells increases tumor progression-associated properties and in vivo tumor growth.
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Trisciuoglio, Daniela, Desideri, Marianna, Ciuffreda, Ludovica, Mottolese, Marcella, Ribatti, Domenico, Vacca, Angelo, Del Rosso, Mario, Marcocci, Lucia, Zupi, Gabriella, and Del Bufalo, Donatella
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CANCER cells , *MELANOMA , *CELL lines , *METALLOPROTEINASES , *TUMOR growth , *PHENOTYPES , *CANCER invasiveness - Abstract
In this study, we demonstrated that bcl-2 overexpression in human melanoma cells consistently enhanced the activity of multiple metastasis-related proteinases, in vitro cell invasion, and in vivo tumor growth. In particular, by using the M14 parental cell line, the MN8 control clone, and two bcl-2 overexpressing derivatives, we found that bcl-2 overexpressing cells exposed to hypoxia, when compared to parental cells, expressed higher level of several metalloproteases (MMPs) such as MMP-2, MMP-7, MT1-MMP, and tissue inhibitors of metalloproteases-1 and -2. Moreover, bcl-2 overexpression in melanoma cells enhanced in vitro invasion on matrigel and, in vivo tumor growth. The more aggressive behavior of bcl-2 transfectants tumors is significantly associated to an increase in MMP-2 expression as well as in a more elevated microvessel density as compared to the parental line. Taken together, our data suggest that bcl-2 plays a pivotal role in the regulation of molecules associated with the migratory and invasive phenotype, contributing, in cooperation to hypoxia, to tumor progression. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
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- 2005
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22. Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb.
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D'Aguanno, Simona, Valentini, Elisabetta, Tupone, Maria Grazia, Desideri, Marianna, Di Martile, Marta, Del Bufalo, Donatella, Trisciuoglio, Daniela, Spagnuolo, Manuela, Rizzo, Maria Giulia, Buglioni, Simonetta, Ercolani, Cristiana, Falcone, Italia, Milella, Michele, De Dominici, Marco, Calabretta, Bruno, Cota, Carlo, and Anichini, Andrea
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SEMAPHORINS ,MELANOMA ,DISEASE progression ,BCL-2 proteins ,MYB gene ,MICRORNA - Abstract
Background: Melanoma, the most aggressive form of skin cancer, is characterized by high rates of metastasis, drug resistance and mortality. Here we investigated the role of Semaphorin 5A (Sema5A) on the properties associated with melanoma progression and the factors involved in Sema5A regulation. Methods: Western blotting, qRT-PCR, Chromatin immunoprecipitation (ChIP) assay, immunohistochemistry of melanoma patient specimens and xenograft tissues, in vitro Transwell assay for cell migration and invasion evaluation, in vitro capillary-like structure formation analysis. Results: A significant correlation of Sema5A mRNA expression and melanoma progression was observed by analyzing GEO profile dataset. Endogenous Sema5A protein was detected in 95% of human melanoma cell lines tested, in 70% of metastatic specimens from patients affected by melanoma, and 16% of in situ melanoma specimens showed a focal positivity. We demonstrated that Sema5A regulates in vitro cell migration and invasion and the formation of vasculogenic structures. We also found an increase of Sema5A at both mRNA and protein level after forced expression of Bcl-2. By use of transcriptional and proteasome inhibitors, we showed that Bcl-2 increases the stability of Sema5A mRNA and protein. Moreover, by ChIP we demonstrated that Sema5A expression is under the control of the transcription factor c-Myb and that c-Myb recruitment on Sema5A promoter is increased after Bcl-2 overexpression. Finally, a concomitant decrease in the expression of Sema5A, Bcl-2 and c-Myb proteins was observed in melanoma cells after miR-204 overexpression. Conclusion: Overall our data provide evidences supporting the role of Sema5A in melanoma progression and the involvement of Bcl-2, miR-204 and c-Myb in regulating its expression. [ABSTRACT FROM AUTHOR]
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- 2018
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23. BCL-XL overexpression promotes tumor progression-associated properties.
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Trisciuoglio, Daniela, Tupone, Maria Grazia, Desideri, Marianna, Di Martile, Marta, Gabellini, Chiara, Buglioni, Simonetta, Pallocca, Matteo, Alessandrini, Gabriele, D’Aguanno, Simona, and Del Bufalo, Donatella
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- 2017
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24. NAADP-Dependent Ca2+ Signaling Controls Melanoma Progression, Metastatic Dissemination and Neoangiogenesis.
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Favia, Annarita, Pafumi, Irene, Desideri, Marianna, Padula, Fabrizio, Montesano, Camilla, Passeri, Daniela, Nicoletti, Carmine, Orlandi, Augusto, Del Bufalo, Donatella, Sergi, Manuel, Ziparo, Elio, Palombi, Fioretta, and Filippini, Antonio
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- 2016
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25. Functional activity of CXCL8 receptors, CXCR1 and CXCR2, on human malignant melanoma progression
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Gabellini, Chiara, Trisciuoglio, Daniela, Desideri, Marianna, Candiloro, Antonio, Ragazzoni, Ylenia, Orlandi, Augusto, Zupi, Gabriella, and Del Bufalo, Donatella
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INTERLEUKIN-8 , *CELL receptors , *MELANOMA , *CELL proliferation , *CELL migration , *NEOVASCULARIZATION , *CELL lines , *GENE expression , *CHEMOTAXIS , *CANCER invasiveness - Abstract
Abstract: We examined the autocrine/paracrine role of interleukin-8 (CXCL8) and the functional significance of CXCL8 receptors, CXCR1 and CXCR2, in human malignant melanoma proliferation, migration, invasion and angiogenesis. We found that a panel of seven cell lines, even though at different extent, secreted CXCL8 protein, and expressed CXCR1 and CXCR2 independently from the CXCL8 expression, but depending on the oxygen level. In fact, hypoxic exposure increases the expression of CXCR1 and CXCR2. The cell proliferation of both M20 and A375SM lines, expressing similar levels of both CXCR1 and CXCR2 but secreting low and high amounts of CXCL8, respectively, was significantly enhanced by CXCL8 exposure and reduced by CXCL8, CXCR1 and CXCR2 neutralising antibodies, indicating the autocrine/paracrine role of CXCL8 in melanoma cell proliferation. Moreover, an increased invasion and migration in response to CXCL8 was observed in several cell lines, and a further enhancement evidenced under hypoxic conditions. A CXCL8-dependent in vivo vessel formation, evaluated through a matrigel assay, was also demonstrated. Furthermore, when neutralising antibodies against CXCR1 or CXCR2 were used, only the involvement of CXCR2, but not CXCR1 was observed on cell migration and invasion, while both receptors played a role in angiogenesis. In summary, our data demonstrate that CXCL8 induces cell proliferation and angiogenesis through both receptors and that CXCR2 plays an important role in regulating the CXCL8-mediated invasive and migratory behaviour of human melanoma cells. Thus, blocking the CXCL8 signalling axis promises an improvement for the therapy of cancer and, in particular, of metastatic melanoma. [Copyright &y& Elsevier]
- Published
- 2009
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26. Growth-Inhibitory and Antiangiogenic Activity of the MEK Inhibitor PD0325901 in Malignant Melanoma with or without BRAF Mutations.
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Ciuffreda, Ludovica, Del Bufalo, Donatella, Desideri, Marianna, Di Sanza, Cristina, Stoppacciaro, Antonella, Ricciardi, Maria Rosaria, Chiaretti, Sabina, Tavolaro, Simona, Benassi, Barbara, Bellacosa, Alfonso, Foà, Robin, Tafuri, Agostino, Cognetti, Francesco, Anichini, Andrea, Zupi, Gabriella, and Milella, Michele
- Subjects
- *
BIOMOLECULES , *NEOVASCULARIZATION inhibitors , *ANTINEOPLASTIC agents , *CELL proliferation , *CANCER cells , *CELL lines , *GENETIC mutation , *PREVENTION - Abstract
The Raf/MEK/ERK pathway is an important mediator of tumor cell proliferation and angiogenesis. Here, we investigated the growth-inhibitory and antiangiogenic properties of PD0325901, a novel MEK inhibitor, in human melanoma cells. PD0325901 effects were determined in a panel of melanoma cell lines with different genetic aberrations. PD0325901 markedly inhibited ERK phosphorylation and growth of both BRAF mutant and wild-type melanoma cell lines, with IC50 in the nanomolar range even in the least responsive models. Growth inhibition was observed both in vitro and in vivo in xenograft models, regardless of BRAF mutation status, and was due to G1-phase cell cycle arrest and subsequent induction of apoptosis. Cell cycle (cyclin D1, c-Myc, and p27KIP1) and apoptosis (Bcl-2 and survivin) regulators were modulated by PD0325901 at the protein level. Gene expression profiling revealed profound modulation of several genes involved in the negative control of MAPK signaling and melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action. Finally, PD0325901 inhibited the production of the proangiogenic factors vascular endothelial growth factor and interleukin 8 at a transcriptional level. In conclusion, PD0325901 exerts potent growth-inhibitory, proapoptotic, and antiangiogenic activity in melanoma lines, regardless of their BRAF mutation status. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective treatment strategies for patients experiencing malignant melanoma. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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27. Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma
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Carlotta Mastroiorio, Virginia Ferraresi, Maria Grazia Tupone, Michele Milella, Donatella Del Bufalo, Nicola Baldini, Marianna Desideri, Rita Falcioni, Simonetta Buglioni, Marta Di Martile, Daniela Trisciuoglio, Roberto Biagini, Barbara Antoniani, Di Martile, Marta, Desideri, Marianna, Tupone, Maria Grazia, Buglioni, Simonetta, Antoniani, Barbara, Mastroiorio, Carlotta, Falcioni, Rita, Ferraresi, Virginia, Baldini, Nicola, Biagini, Roberto, Milella, Michele, Trisciuoglio, Daniela, and Del Bufalo, Donatella
- Subjects
0301 basic medicine ,Cancer Research ,Programmed cell death ,sarcoma ,medicine.drug_class ,lcsh:RC254-282 ,Article ,combination therapy ,03 medical and health sciences ,0302 clinical medicine ,HDAC inhibitor ,Medicine ,Doxorubicin ,Molecular Biology ,business.industry ,Histone deacetylase inhibitor, apoptosis, sarcoma, epigenetics ,Histone deacetylase inhibitor ,Autophagy ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,Histone ,030104 developmental biology ,Apoptosis ,030220 oncology & carcinogenesis ,FOXO4 ,Cancer research ,Histone deacetylase ,Sarcoma ,business ,medicine.drug - Abstract
Sarcomas are rare tumors with generally poor prognosis, for which current therapies have shown limited efficacy. Histone deacetylase inhibitors (HDACi) are emerging anti-tumor agents; however, little is known about their effect in sarcomas. By using established and patient-derived sarcoma cells with different subtypes, we showed that the pan-HDACi, ITF2357, potently inhibited in vitro survival in a p53-independent manner. ITF2357-mediated cell death implied the activation of mitochondrial apoptosis, as attested by induction of pro-apoptotic BH3-only proteins and a caspases-dependent mechanism. ITF2357 also induced autophagy, which protected sarcoma cells from apoptotic cell death. ITF2357 activated forkhead box (FOXO) 1 and 3a transcription factors and their downstream target genes, however, silencing of both FOXO1 and 3a did not protect sarcoma cells against ITF2357-induced apoptosis and upregulated FOXO4 and 6. Notably, ITF2357 synergized with Doxorubicin to induce cell death of established and patient-derived sarcoma cells. Furthermore, combination treatment strongly impaired xenograft tumor growth in vivo, when compared to single treatments, suggesting that combination of ITF2357 with Doxorubicin has the potential to enhance sensitization in different preclinical models of sarcoma. Overall, our study highlights the therapeutic potential of ITF2357, alone or in rational combination therapies, for bone and soft tissue sarcomas management.
- Published
- 2018
28. Melanoma-specific bcl-2 promotes a protumoral M2-like phenotype by tumor-associated macrophages.
- Author
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Di Martile M, Farini V, Consonni FM, Trisciuoglio D, Desideri M, Valentini E, D'Aguanno S, Tupone MG, Buglioni S, Ercolani C, Gallo E, Amadio B, Terrenato I, Foddai ML, Sica A, and Del Bufalo D
- Subjects
- Animals, Apoptosis, Cell Differentiation, Cell Movement, Cell Proliferation, Female, Humans, Melanoma immunology, Melanoma metabolism, Mice, Mice, Inbred C57BL, Phenotype, Tumor Cells, Cultured, Tumor-Associated Macrophages immunology, Xenograft Model Antitumor Assays, Melanoma pathology, Monocytes immunology, Proto-Oncogene Proteins c-bcl-2 metabolism, Tumor Microenvironment immunology, Tumor-Associated Macrophages pathology
- Abstract
Background: A bidirectional crosstalk between tumor cells and the surrounding microenvironment contributes to tumor progression and response to therapy. Our previous studies have demonstrated that bcl-2 affects melanoma progression and regulates the tumor microenvironment. The aim of this study was to evaluate whether bcl-2 expression in melanoma cells could influence tumor-promoting functions of tumor-associated macrophages, a major constituent of the tumor microenvironment that affects anticancer immunity favoring tumor progression., Methods: THP-1 monocytic cells, monocyte-derived macrophages and melanoma cells expressing different levels of bcl-2 protein were used. ELISA, qRT-PCR and Western blot analyses were used to evaluate macrophage polarization markers and protein expression levels. Chromatin immunoprecipitation assay was performed to evaluate transcription factor recruitment at specific promoters. Boyden chamber was used for migration experiments. Cytofluorimetric and immunohistochemical analyses were carried out to evaluate infiltrating macrophages and T cells in melanoma specimens from patients or mice., Results: Higher production of tumor-promoting and chemotactic factors, and M2-polarized activation was observed when macrophages were exposed to culture media from melanoma cells overexpressing bcl-2, while bcl-2 silencing in melanoma cells inhibited the M2 macrophage polarization. In agreement, the number of melanoma-infiltrating macrophages in vivo was increased, in parallel with a greater expression of bcl-2 in tumor cells. Tumor-derived interleukin-1β has been identified as the effector cytokine of bcl-2-dependent macrophage reprogramming, according to reduced tumor growth, decreased number of M2-polarized tumor-associated macrophages and increased number of infiltrating CD4
+ IFNγ+ and CD8+ IFNγ+ effector T lymphocytes, which we observed in response to in vivo treatment with the IL-1 receptor antagonist kineret. Finally, in tumor specimens from patients with melanoma, high bcl-2 expression correlated with increased infiltration of M2-polarized CD163+ macrophages, hence supporting the clinical relevance of the crosstalk between tumor cells and microenvironment., Conclusions: Taken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2020
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29. Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma.
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Fianco G, Mongiardi MP, Levi A, De Luca T, Desideri M, Trisciuoglio D, Del Bufalo D, Cinà I, Di Benedetto A, Mottolese M, Gentile A, Centonze D, Ferrè F, and Barilà D
- Subjects
- Cytokines metabolism, Gene Expression Profiling, Glioblastoma pathology, Humans, Microarray Analysis, NF-kappa B metabolism, Neovascularization, Pathologic pathology, Prognosis, Vascular Endothelial Growth Factor A metabolism, Caspase 8 metabolism, Drug Resistance, Neoplasm, Glioblastoma physiopathology, Neovascularization, Pathologic physiopathology
- Abstract
Caspase-8 is a key player in extrinsic apoptosis and its activity is often downregulated in cancer. However, human Caspase-8 expression is retained in some tumors, including glioblastoma (GBM), suggesting that it may support cancer growth in these contexts. GBM, the most aggressive of the gliomas, is characterized by extensive angiogenesis and by an inflammatory microenvironment that support its development and resistance to therapies. We have recently shown that Caspase-8 sustains neoplastic transformation in vitro in human GBM cell lines. Here, we demonstrate that Caspase-8, through activation of NF-kB, enhances the expression and secretion of VEGF, IL-6, IL-8, IL-1beta and MCP-1, leading to neovascularization and increased resistance to Temozolomide. Importantly, the bioinformatics analysis of microarray gene expression data derived from a set of high-grade human gliomas, shows that high Caspase-8 expression levels correlate with a worse prognosis.
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- 2017
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30. Histone acetyltransferase inhibitor CPTH6 preferentially targets lung cancer stem-like cells.
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Di Martile M, Desideri M, De Luca T, Gabellini C, Buglioni S, Eramo A, Sette G, Milella M, Rotili D, Mai A, Carradori S, Secci D, De Maria R, Del Bufalo D, and Trisciuoglio D
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung pathology, Cell Differentiation drug effects, Cell Line, Tumor, Cell Survival drug effects, Female, Histone Acetyltransferases metabolism, Humans, Lung Neoplasms enzymology, Lung Neoplasms pathology, Mice, Mice, Inbred NOD, Mice, SCID, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells enzymology, Neoplastic Stem Cells pathology, Xenograft Model Antitumor Assays, Carcinoma, Non-Small-Cell Lung drug therapy, Histone Acetyltransferases antagonists & inhibitors, Lung Neoplasms drug therapy, Thiazoles pharmacology
- Abstract
Cancer stem cells (CSCs) play an important role in tumor initiation, progression, therapeutic failure and tumor relapse. In this study, we evaluated the efficacy of the thiazole derivative 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6), a novel pCAF and Gcn5 histone acetyltransferase inhibitor, as a small molecule that preferentially targets lung cancer stem-like cells (LCSCs) derived from non-small cell lung cancer (NSCLC) patients. Notably, although CPTH6 inhibits the growth of both LCSC and NSCLC cell lines, LCSCs exhibit greater growth inhibition than established NSCLC cells. Growth inhibitory effect of CPTH6 in LCSC lines is primarily due to apoptosis induction. Of note, differentiated progeny of LCSC lines is more resistant to CPTH6 in terms of loss of cell viability and reduction of protein acetylation, when compared to their undifferentiated counterparts. Interestingly, in LCSC lines CPTH6 treatment is also associated with a reduction of stemness markers. By using different HAT inhibitors we provide clear evidence that inhibition of HAT confers a strong preferential inhibitory effect on cell viability of undifferentiated LCSC lines when compared to their differentiated progeny. In vivo, CPTH6 is able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors, as evidenced by marked reduction of tumor-initiating capacity in limiting dilution assays. Strikingly, the ability of CPTH6 to inhibit tubulin acetylation is also confirmed in vivo. Overall, our studies propose histone acetyltransferase inhibition as an attractive target for cancer therapy of NSCLC.
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- 2016
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31. NAADP-Dependent Ca(2+) Signaling Controls Melanoma Progression, Metastatic Dissemination and Neoangiogenesis.
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Favia A, Pafumi I, Desideri M, Padula F, Montesano C, Passeri D, Nicoletti C, Orlandi A, Del Bufalo D, Sergi M, Ziparo E, Palombi F, and Filippini A
- Subjects
- Animals, Carbolines pharmacokinetics, Carbolines pharmacology, Carbolines toxicity, Cell Adhesion drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Disease Models, Animal, Disease Progression, Gene Expression, Male, Melanoma drug therapy, Melanoma genetics, Melanoma, Experimental, Mice, NADP metabolism, Neoplasm Metastasis, Neovascularization, Pathologic drug therapy, Piperazines pharmacokinetics, Piperazines pharmacology, Piperazines toxicity, Tumor Burden drug effects, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A pharmacology, Vascular Endothelial Growth Factor Receptor-2 genetics, Vascular Endothelial Growth Factor Receptor-2 metabolism, Calcium Signaling drug effects, Melanoma metabolism, Melanoma pathology, NADP analogs & derivatives, Neovascularization, Pathologic metabolism
- Abstract
A novel transduction pathway for the powerful angiogenic factor VEGF has been recently shown in endothelial cells to operate through NAADP-controlled intracellular release of Ca(2+). In the present report the possible involvement of NAADP-controlled Ca(2+) signaling in tumor vascularization, growth and metastatic dissemination was investigated in a murine model of VEGF-secreting melanoma. Mice implanted with B16 melanoma cells were treated with NAADP inhibitor Ned-19 every second day for 4 weeks and tumor growth, vascularization and metastatization were evaluated. Control specimens developed well vascularized tumors and lung metastases, whereas in Ned-19-treated mice tumor growth and vascularization as well as lung metastases were strongly inhibited. In vitro experiments showed that Ned-19 treatment controls the growth of B16 cells in vitro, their migratory ability, adhesive properties and VEGFR2 expression, indicating NAADP involvement in intercellular autocrine signaling. To this regard, Ca(2+) imaging experiments showed that the response of B16 cells to VEGF stimulation is NAADP-dependent. The whole of these observations indicate that NAADP-controlled Ca(2+) signaling can be relevant not only for neoangiogenesis but also for direct control of tumor cells.
- Published
- 2016
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32. CPTH6, a thiazole derivative, induces histone hypoacetylation and apoptosis in human leukemia cells.
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Trisciuoglio D, Ragazzoni Y, Pelosi A, Desideri M, Carradori S, Gabellini C, Maresca G, Nescatelli R, Secci D, Bolasco A, Bizzarri B, Cavaliere C, D'Agnano I, Filetici P, Ricci-Vitiani L, Rizzo MG, and Del Bufalo D
- Subjects
- Acetylation, Animals, Antineoplastic Agents adverse effects, Apoptosis Regulatory Proteins metabolism, Cell Cycle drug effects, Cell Differentiation drug effects, Cell Line, Tumor, Cell Survival drug effects, Humans, Leukemia, Myeloid, Acute, Mice, Neuroblastoma, Thiazoles adverse effects, Tubulin metabolism, Antineoplastic Agents pharmacology, Apoptosis drug effects, Histones metabolism, Protein Processing, Post-Translational drug effects, Thiazoles pharmacology, p300-CBP Transcription Factors antagonists & inhibitors
- Abstract
Purpose: We previously identified novel thiazole derivatives able to reduce histone acetylation and histone acetyltransferase (HAT) activity in yeast. Among these compounds, 3-methylcyclopentylidene-[4-(4'-chlorophenyl)thiazol-2-yl]hydrazone (CPTH6) has been selected and used throughout this study., Experimental Design: The effect of CPTH6 on histone acetylation, cell viability and differentiation, cell-cycle distribution, and apoptosis in a panel of acute myeloid leukemia and solid tumor cell lines has been evaluated., Results: Here, we showed that CPTH6 leads to an inhibition of Gcn5 and pCAF HAT activity. Moreover, it inhibits H3/H4 histones and α-tubulin acetylation of a panel of leukemia cell lines. Concentration- and time-dependent inhibition of cell viability, paralleled by accumulation of cells in the G(0)/G(1) phase and depletion from the S/G(2)M phases, was observed. The role of mitochondrial pathway on CPTH6-induced apoptosis was shown, being a decrease of mitochondrial membrane potential and the release of cytochrome c, from mitochondria to cytosol, induced by CPTH6. Also the involvement of Bcl-2 and Bcl-xL on CPTH6-induced apoptosis was found after overexpression of the two proteins in leukemia cells. Solid tumor cell lines from several origins were shown to be differently sensitive to CPTH6 treatment in terms of cell viability, and a correlation between the inhibitory efficacy on H3/H4 histones acetylation and cytotoxicity was found. Differentiating effect on leukemia and neuroblastoma cell lines was also induced by CPTH6., Conclusions: These results make CPTH6 a suitable tool for discovery of molecular targets of HAT and, potentially, for the development of new anticancer therapies, which warrants further investigations., (©2011 AACR.)
- Published
- 2012
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33. Modulation of bcl-xL in tumor cells regulates angiogenesis through CXCL8 expression.
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Giorgini S, Trisciuoglio D, Gabellini C, Desideri M, Castellini L, Colarossi C, Zangemeister-Wittke U, Zupi G, and Del Bufalo D
- Subjects
- Biomarkers, Tumor metabolism, Blotting, Northern, Blotting, Western, Cells, Cultured, Collagen, Drug Combinations, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Glioblastoma drug therapy, Glioblastoma pathology, Humans, Interleukin-8 genetics, Laminin, Melanoma, Experimental drug therapy, Melanoma, Experimental pathology, Promoter Regions, Genetic, Protein Array Analysis, Proteoglycans, RNA, Messenger genetics, RNA, Messenger metabolism, Umbilical Veins, bcl-X Protein genetics, Glioblastoma blood supply, Interleukin-8 metabolism, Melanoma, Experimental blood supply, Neovascularization, Pathologic metabolism, Oligonucleotides, Antisense pharmacology, bcl-X Protein metabolism
- Abstract
In this paper, we investigated whether bcl-xL can be involved in the modulation of the angiogenic phenotype of human tumor cells. Using the ADF human glioblastoma and the M14 melanoma lines, and their derivative bcl-xL-overexpressing clones, we showed that the conditioned medium of bcl-xL transfectants increased in vitro endothelial cell functions, such as proliferation and morphogenesis, and in vivo vessel formation in Matrigel plugs, compared with the conditioned medium of control cells. Moreover, the overexpression of bcl-xL induced an increased expression of the proangiogenic interleukin-8 (CXCL8), both at the protein and mRNA levels, and an enhanced CXCL8 promoter activity. The role of CXCL8 on bcl-xL-induced angiogenesis was validated using CXCL8-neutralizing antibodies, whereas down-regulation of bcl-xL through antisense oligonucleotide or RNA interference strategies confirmed the involvement of bcl-xL on CXCL8 expression. Transient overexpression of bcl-xL led to extend this observation to other tumor cell lines with different origin, such as colon and prostate carcinoma. In conclusion, our results showed that CXCL8 modulation by bcl-xL regulates tumor angiogenesis, and they point to elucidate an additional function of bcl-xL protein.
- Published
- 2007
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34. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus.
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Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, and Milella M
- Subjects
- Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Growth Processes drug effects, Cell Line, Tumor, Enzyme-Linked Immunosorbent Assay, Humans, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Protein Kinases metabolism, Sirolimus pharmacology, TOR Serine-Threonine Kinases, Vascular Endothelial Growth Factor A biosynthesis, Angiogenesis Inhibitors pharmacology, Breast Neoplasms blood supply, Breast Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Sirolimus analogs & derivatives
- Abstract
Mammalian target of rapamycin (mTOR) is increasingly recognized as a master regulator of fundamental cellular functions, whose deregulation may underlie neoplastic transformation and progression. Hence, mTOR has recently emerged as a promising target for therapeutic anticancer interventions in several human tumors, including breast cancer. Here, we investigated the antiangiogenic potential of temsirolimus (also known as CCI-779), a novel mTOR inhibitor currently in clinical development for the treatment of breast cancer and other solid tumors. Consistent with previous reports, sensitivity to temsirolimus-mediated growth inhibition varied widely among different breast cancer cell lines and was primarily due to inhibition of proliferation with little, if any, effect on apoptosis induction. In the HER-2 gene-amplified breast cancer cell line BT474, temsirolimus inhibited vascular endothelial growth factor (VEGF) production in vitro under both normoxic and hypoxic conditions through inhibition of hypoxia-stimulated hypoxia-inducible factor (HIF)-1alpha expression and transcriptional activation. Interestingly, these effects were also observed in the MDA-MB-231 cell line, independent of its inherent sensitivity to the growth-inhibitory effects of temsirolimus. A central role for mTOR (and the critical regulator of cap-dependent protein translation, eIF4E) in the regulation of VEGF production by BT474 cells was further confirmed using a small interfering RNA approach to silence mTOR and eIF4E protein expression. In addition to its effect on HIF-1alpha-mediated VEGF production, temsirolimus also directly inhibited serum- and/or VEGF-driven endothelial cell proliferation and morphogenesis in vitro and vessel formation in a Matrigel assay in vivo. Overall, these results suggest that antiangiogenic effects may substantially contribute to the antitumor activity observed with temsirolimus in breast cancer.
- Published
- 2006
- Full Text
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