13 results on '"Fazli, L."'
Search Results
2. CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer.
- Author
-
Tsujino T, Takai T, Hinohara K, Gui F, Tsutsumi T, Bai X, Miao C, Feng C, Gui B, Sztupinszki Z, Simoneau A, Xie N, Fazli L, Dong X, Azuma H, Choudhury AD, Mouw KW, Szallasi Z, Zou L, Kibel AS, and Jia L
- Subjects
- Humans, Male, BRCA1 Protein metabolism, DNA Repair genetics, Genes, BRCA2, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Drug Resistance, Neoplasm, Antineoplastic Agents pharmacology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics
- Abstract
Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53-dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
3. Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer.
- Author
-
Al-Nakouzi N, Wang CK, Oo HZ, Nelepcu I, Lallous N, Spliid CB, Khazamipour N, Lo J, Truong S, Collins C, Hui D, Esfandnia S, Adomat H, Clausen TM, Gustavsson T, Choudhary S, Dagil R, Corey E, Wang Y, Chauchereau A, Fazli L, Esko JD, Salanti A, Nelson PS, Gleave ME, and Daugaard M
- Subjects
- Androgens, Chondroitin Sulfates, Glycocalyx metabolism, Humans, Male, Signal Transduction, Tumor Microenvironment, Prostatic Neoplasms, Castration-Resistant drug therapy
- Abstract
Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
4. A noncanonical AR addiction drives enzalutamide resistance in prostate cancer.
- Author
-
He Y, Wei T, Ye Z, Orme JJ, Lin D, Sheng H, Fazli L, Jeffrey Karnes R, Jimenez R, Wang L, Wang L, Gleave ME, Wang Y, Shi L, and Huang H
- Subjects
- Androgen Antagonists pharmacology, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors pharmacology, Animals, Benzamides, Binding Sites, Cell Proliferation drug effects, DNA-Binding Proteins metabolism, Hepatocyte Nuclear Factor 3-alpha metabolism, Humans, Male, Mice, Mice, SCID, Nitriles, Organoids, Prostatic Neoplasms drug therapy, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Signal Transduction drug effects, Transcription Factors metabolism, Up-Regulation, Xenograft Model Antitumor Assays, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Prostatic Neoplasms metabolism, Receptors, Androgen metabolism
- Abstract
Resistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.
- Published
- 2021
- Full Text
- View/download PDF
5. Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer.
- Author
-
Vandekerkhove G, Lavoie JM, Annala M, Murtha AJ, Sundahl N, Walz S, Sano T, Taavitsainen S, Ritch E, Fazli L, Hurtado-Coll A, Wang G, Nykter M, Black PC, Todenhöfer T, Ost P, Gibb EA, Chi KN, Eigl BJ, and Wyatt AW
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Carcinoma, Transitional Cell genetics, Female, Humans, Male, Middle Aged, Mutation, Prognosis, Receptor, ErbB-2 genetics, Retrospective Studies, Survival Analysis, Urinary Bladder, Xeroderma Pigmentosum Group D Protein genetics, Circulating Tumor DNA blood, Genomics, Plasma, Urinary Bladder Neoplasms blood, Urinary Bladder Neoplasms genetics
- Abstract
Molecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.
- Published
- 2021
- Full Text
- View/download PDF
6. Histone demethylase JMJD1A promotes expression of DNA repair factors and radio-resistance of prostate cancer cells.
- Author
-
Fan L, Xu S, Zhang F, Cui X, Fazli L, Gleave M, Clark DJ, Yang A, Hussain A, Rassool F, and Qi J
- Subjects
- Animals, DNA Breaks, Double-Stranded, Disease Models, Animal, Gene Expression, Gene Knockdown Techniques, Humans, Jumonji Domain-Containing Histone Demethylases genetics, Male, Mice, PC-3 Cells, Prostatic Neoplasms, Castration-Resistant genetics, Prostatic Neoplasms, Castration-Resistant metabolism, Rad51 Recombinase metabolism, Radiation Tolerance, Random Allocation, Transfection, Tumor Suppressor p53-Binding Protein 1 metabolism, Xenograft Model Antitumor Assays, DNA Repair, Jumonji Domain-Containing Histone Demethylases metabolism, Prostatic Neoplasms, Castration-Resistant radiotherapy
- Abstract
The DNA damage response (DDR) pathway is a promising target for anticancer therapies. The androgen receptor and myeloblastosis transcription factors have been reported to regulate expression of an overlapping set of DDR genes in prostate cancer cells. Here, we found that histone demethylase JMJD1A regulates expression of a different set of DDR genes largely through c-Myc. Inhibition of JMJD1A delayed the resolution of γ-H2AX foci, reduced the formation of foci containing ubiquitin, 53BP1, BRCA1 or Rad51, and inhibited the reporter activity of double-strand break (DSB) repair. Mechanistically, JMJD1A regulated expression of DDR genes by increasing not only the level but also the chromatin recruitment of c-Myc through H3K9 demethylation. Further, we found that ubiquitin ligase HUWE1 induced the K27-/K29-linked noncanonical ubiquitination of JMJD1A at lysine-918. Ablation of the JMJD1A noncanonical ubiquitination lowered DDR gene expression, impaired DSB repair, and sensitized response of prostate cells to irradiation, topoisomerase inhibitors or PARP inhibitors. Thus, development of agents that target JMJD1A or its noncanonical ubiquitination may sensitize the response of prostate cancer to radiotherapy and possibly also genotoxic therapy.
- Published
- 2020
- Full Text
- View/download PDF
7. Author Correction: Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.
- Author
-
Korpal M, Puyang X, Wu ZJ, Seiler R, Furman C, Oo HZ, Seiler M, Irwin S, Subramanian V, Joshi JJ, Wang CK, Rimkunas V, Tortora D, Yang H, Kumar N, Kuznetsov G, Matijevic M, Chow J, Kumar P, Zou J, Feala J, Corson L, Henry R, Selvaraj A, Davis A, Bloudoff K, Douglas J, Kiss B, Roberts M, Fazli L, Black PC, Fekkes P, Smith PG, Warmuth M, Yu L, Hao MH, Larsen N, Daugaard M, and Zhu P
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2019
- Full Text
- View/download PDF
8. IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling.
- Author
-
Sheng X, Nenseth HZ, Qu S, Kuzu OF, Frahnow T, Simon L, Greene S, Zeng Q, Fazli L, Rennie PS, Mills IG, Danielsen H, Theis F, Patterson JB, Jin Y, and Saatcioglu F
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Benzopyrans chemistry, Benzopyrans therapeutic use, Cell Line, Tumor, Cell Survival, Endoribonucleases antagonists & inhibitors, Endoribonucleases genetics, Humans, Male, Mice, Mice, Nude, Morpholines chemistry, Morpholines therapeutic use, Prostatic Neoplasms drug therapy, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins c-myc genetics, Random Allocation, Antineoplastic Agents pharmacology, Benzopyrans pharmacology, Endoribonucleases metabolism, Gene Expression Regulation, Neoplastic drug effects, Morpholines pharmacology, Prostatic Neoplasms metabolism, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins c-myc metabolism, Signal Transduction physiology, X-Box Binding Protein 1 metabolism
- Abstract
Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.
- Published
- 2019
- Full Text
- View/download PDF
9. ONECUT2 is a driver of neuroendocrine prostate cancer.
- Author
-
Guo H, Ci X, Ahmed M, Hua JT, Soares F, Lin D, Puca L, Vosoughi A, Xue H, Li E, Su P, Chen S, Nguyen T, Liang Y, Zhang Y, Xu X, Xu J, Sheahan AV, Ba-Alawi W, Zhang S, Mahamud O, Vellanki RN, Gleave M, Bristow RG, Haibe-Kains B, Poirier JT, Rudin CM, Tsao MS, Wouters BG, Fazli L, Feng FY, Ellis L, van der Kwast T, Berlin A, Koritzinsky M, Boutros PC, Zoubeidi A, Beltran H, Wang Y, and He HH
- Subjects
- Animals, Carcinogenesis genetics, Carcinogenesis pathology, Cell Hypoxia drug effects, Cell Hypoxia genetics, Cell Line, Tumor, Cell Proliferation drug effects, Datasets as Topic, Disease Progression, Gene Expression Profiling, Homeodomain Proteins genetics, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neuroendocrine Tumors pathology, Nitroimidazoles pharmacology, Phosphoramide Mustards pharmacology, Prostate pathology, Prostatic Neoplasms pathology, RNA, Small Interfering metabolism, Signal Transduction genetics, Smad3 Protein metabolism, Transcription Factors genetics, Up-Regulation, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, Homeodomain Proteins metabolism, Neuroendocrine Tumors genetics, Prostatic Neoplasms genetics, Smad3 Protein genetics, Transcription Factors metabolism
- Abstract
Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.
- Published
- 2019
- Full Text
- View/download PDF
10. Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer.
- Author
-
Korpal M, Puyang X, Jeremy Wu Z, Seiler R, Furman C, Oo HZ, Seiler M, Irwin S, Subramanian V, Julie Joshi J, Wang CK, Rimkunas V, Tortora D, Yang H, Kumar N, Kuznetsov G, Matijevic M, Chow J, Kumar P, Zou J, Feala J, Corson L, Henry R, Selvaraj A, Davis A, Bloudoff K, Douglas J, Kiss B, Roberts M, Fazli L, Black PC, Fekkes P, Smith PG, Warmuth M, Yu L, Hao MH, Larsen N, Daugaard M, and Zhu P
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cell Line, Tumor, Cytokines genetics, Cytokines immunology, Cytokines metabolism, Gene Expression Profiling methods, HCT116 Cells, Humans, Immunoblotting, Immunotherapy methods, Inflammation Mediators immunology, Inflammation Mediators metabolism, Mice, Microscopy, Fluorescence, Mutation immunology, Neoplasm Invasiveness, PPAR gamma chemistry, PPAR gamma genetics, Protein Multimerization immunology, Retinoid X Receptor alpha chemistry, Retinoid X Receptor alpha genetics, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms therapy, Immune Evasion immunology, Monitoring, Immunologic, PPAR gamma immunology, Retinoid X Receptor alpha immunology, Urinary Bladder Neoplasms immunology
- Abstract
Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγ
High /RXRαS427F/Y impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic "immuno-oncogenes" that modulate the immune microenvironment of cancer.Muscle-invasive bladder cancer (MIBC) is a potentially lethal disease. Here the authors characterize diverse genetic alterations in MIBC that convergently lead to constitutive activation of PPARgamma/RXRalpha and result in immunosurveillance escape by inhibiting CD8+ T-cell recruitment.- Published
- 2017
- Full Text
- View/download PDF
11. DAB2IP loss confers the resistance of prostate cancer to androgen deprivation therapy through activating STAT3 and inhibiting apoptosis.
- Author
-
Zhou J, Ning Z, Wang B, Yun EJ, Zhang T, Pong RC, Fazli L, Gleave M, Zeng J, Fan J, Wang X, Li L, Hsieh JT, He D, and Wu K
- Subjects
- Animals, Apoptosis, Castration, Cytochromes c metabolism, Gene Deletion, HEK293 Cells, Humans, Inhibitor of Apoptosis Proteins metabolism, Male, Membrane Potential, Mitochondrial genetics, Mice, Mice, Nude, Phosphorylation, Prostatic Neoplasms, Castration-Resistant pathology, Repressor Proteins metabolism, STAT3 Transcription Factor metabolism, STAT3 Transcription Factor physiology, Signal Transduction genetics, Survivin, ras GTPase-Activating Proteins metabolism, ras GTPase-Activating Proteins physiology, Prostatic Neoplasms, Castration-Resistant genetics, ras GTPase-Activating Proteins genetics
- Abstract
Loss of DAB2IP, a novel tumor suppressor gene, is associated with the high risk of aggressive prostate cancer (PCa). Previously, we reported that DAB2IP modulated androgen receptor activation in the development of castration-resistant PCa; however, its direct action on the failure of androgen deprivation therapy (ADT) remains largely unknown. In this study, we showed that DAB2IP knockdown could significantly enhance in vitro growth and colony formation of PCa cells following ADT as well as tumorigenicity in pre-castrated nude mice. In addition, DAB2IP loss stabilized mitochondrial transmembrane potential, prevented release of cytochrome c, Omi/HtrA2 and Smac from the mitochondria to the cytoplasm and inhibited intrinsic apoptosis induced by ADT. Mechanistically, DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells. Moreover, the luminal epithelia in DAB2IP(-/-) mice with more activated STAT3 and survivin expression were resistant to castration-induced apoptosis. Consistently, DAB2IP expression inversely correlated with STAT3 phosphorylation and survivin expression in PCa patients. Together, our data indicate that DAB2IP loss reprograms intracellular signal transduction and anti-apoptotic gene expression, which potentiates PCa cell survival from ADT-induced cell death.
- Published
- 2015
- Full Text
- View/download PDF
12. Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival.
- Author
-
Zhang F, Kumano M, Beraldi E, Fazli L, Du C, Moore S, Sorensen P, Zoubeidi A, and Gleave ME
- Subjects
- Animals, Apoptosis drug effects, Apoptosis genetics, Autophagy drug effects, Autophagy genetics, Autophagy-Related Proteins, Cell Line, Tumor, Cell Survival drug effects, Clusterin antagonists & inhibitors, Clusterin deficiency, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Humans, Lipid Metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Nude, Microtubule-Associated Proteins antagonists & inhibitors, Microtubule-Associated Proteins metabolism, Phagosomes drug effects, Phagosomes pathology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Pyrimidines pharmacology, Pyrroles pharmacology, Signal Transduction, Thionucleotides genetics, Thionucleotides metabolism, Ubiquitin-Conjugating Enzymes genetics, Ubiquitin-Conjugating Enzymes metabolism, Xenograft Model Antitumor Assays, Clusterin genetics, Gene Expression Regulation, Neoplastic, Microtubule-Associated Proteins genetics, Phagosomes metabolism, Prostatic Neoplasms genetics
- Abstract
We define stress-induced adaptive survival pathways linking autophagy with the molecular chaperone clusterin (CLU) that function to promote anticancer treatment resistance. During treatment stress, CLU co-localizes with LC3 via an LIR-binding sequence within autophagosome membranes, functioning to facilitate LC3-Atg3 heterocomplex stability and LC3 lipidation, and thereby enhance autophagosome biogenesis and autophagy activation. Stress-induced autophagy is attenuated with CLU silencing in CLU(-/-) mice and human prostate cancer cells. CLU-enhanced cell survival occurs via autophagy-dependent pathways, and is reduced following autophagy inhibition. Combining CLU inhibition with anticancer treatments attenuates autophagy activation, increases apoptosis and reduces prostate cancer growth. This study defines a novel adaptor protein function for CLU under stress conditions, and highlights how co-targeting CLU and autophagy can amplify proteotoxic stress to delay cancer progression.
- Published
- 2014
- Full Text
- View/download PDF
13. Lyn tyrosine kinase regulates androgen receptor expression and activity in castrate-resistant prostate cancer.
- Author
-
Zardan A, Nip KM, Thaper D, Toren P, Vahid S, Beraldi E, Fazli L, Lamoureux F, Gust KM, Cox ME, Bishop JL, and Zoubeidi A
- Abstract
Castrate-resistant prostate cancer (CRPC) progression is a complex process by which prostate cells acquire the ability to survive and proliferate in the absence or under very low levels of androgens. Most CRPC tumors continue to express the androgen receptor (AR) as well as androgen-responsive genes owing to reactivation of AR. Protein tyrosine kinases have been implicated in supporting AR activation under castrate conditions. Here we report that Lyn tyrosine kinase expression is upregulated in CRPC human specimens compared with hormone naive or normal tissue. Lyn overexpression enhanced AR transcriptional activity both in vitro and in vivo and accelerated CRPC. Reciprocally, specific targeting of Lyn resulted in a decrease of AR transcriptional activity in vitro and in vivo and prolonged time to castration. Mechanistically, we found that targeting Lyn kinase induces AR dissociation from the molecular chaperone Hsp90, leading to its ubiquitination and proteasomal degradation. This work indicates a novel mechanism of regulation of AR stability and transcriptional activity by Lyn and justifies further investigation of the Lyn tyrosine kinase as a therapeutic target for the treatment of CRPC.Oncogenesis (2014) 3, e115; doi:10.1038/oncsis.2014.30; published online 18 August 2014.
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.