YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer
TL;DR: Zhang et al. as discussed by the authors identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells, and the expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels.
Abstract: Metastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.
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TL;DR: A review of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein-protein interaction (PPI) with TEAD1-4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP 1/TZ-dependent transcription in cancer as mentioned in this paper.
Abstract: The Hippo pathway is an evolutionary conserved signaling network that regulates essential processes such as organ size, cell proliferation, migration, stemness and apoptosis. Alterations in this pathway are commonly found in solid tumors and can lead to hyperproliferation, resistance to chemotherapy, compensation for mKRAS and tumor immune evasion. As the terminal effectors of the Hippo pathway, the transcriptional coactivators YAP1/TAZ and the transcription factors TEAD1–4 present exciting opportunities to pharmacologically modulate the Hippo biology in cancer settings, inflammation and regenerative medicine. This review will provide an overview of the progress and current strategies to directly and indirectly target the YAP1/TAZ protein–protein interaction (PPI) with TEAD1–4 across multiple modalities, with focus on recent small molecules able to selectively bind to TEAD, block its autopalmitoylation and inhibit YAP1/TAZ–TEAD-dependent transcription in cancer.
28 citations
TL;DR: EVs are suggested as promising targets and engineered as nanovehicles to deliver drugs for overcoming drug resistance in cancer therapy and are regarded as novel biomarkers for monitoring therapy response and predicting prognosis.
Abstract: Extracellular vesicles (EVs) are cell‐derived nanosized vesicles that mediate cell‐to‐cell communication via transporting bioactive molecules and thus are critically involved in various physiological and pathological conditions. EVs contribute to different aspects of cancer progression, such as cancer growth, angiogenesis, metastasis, immune evasion, and drug resistance. EVs induce the resistance of cancer cells to chemotherapy, radiotherapy, targeted therapy, antiangiogenesis therapy, and immunotherapy by transferring specific cargos that affect drug efflux and regulate signaling pathways associated with epithelial‐mesenchymal transition, autophagy, metabolism, and cancer stemness. In addition, EVs modulate the reciprocal interaction between cancer cells and noncancer cells in the tumor microenvironment (TME) to develop therapy resistance. EVs are detectable in many biofluids of cancer patients, and thus are regarded as novel biomarkers for monitoring therapy response and predicting prognosis. Moreover, EVs are suggested as promising targets and engineered as nanovehicles to deliver drugs for overcoming drug resistance in cancer therapy. In this review, the biological roles of EVs and their mechanisms of action in cancer drug resistance are summarized. The preclinical studies on using EVs in monitoring and overcoming cancer drug resistance are also discussed.
8 citations
01 Jan 2021
TL;DR: The Hippo pathway core kinases MST1/2 and LATS 1/2 in mammals phosphorylate and inactivate YAP1 signaling to prevent cancer growth.
Abstract: The Hippo pathway controls several biological processes, including cell growth, differentiation, motility, stemness, cell contact, immune cell maturation, organ size, and tumorigenesis. The Hippo pathway core kinases MST1/2 and LATS1/2 in mammals phosphorylate and inactivate YAP1 signaling. Increasing evidence indicates that loss of MST1/2 and LATS1/2 function is linked to the biology of many cancer types with poorer outcomes, likely due to the activation of oncogenic YAP1/TEAD signaling. Therefore, there is a renewed interest in blocking the YAP1/TEAD functions to prevent cancer growth. This review introduces the Hippo pathway components and examines their role and therapeutic potentials in prostate, kidney, and bladder cancer.
4 citations
TL;DR: In this paper, the role of extracellular vesicles (EVs) in therapeutic resistance of advanced prostate cancer and their use to find biomarkers able to predict these resistances was discussed.
Abstract: Prostate cancer (PCa) is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. At first, advanced PCa is treated by androgen deprivation therapy with a good initial response. Nevertheless, recurrences occur, leading to Castrate-Resistance Prostate Cancer (CRPC). During the last decade, new therapies based on inhibition of the androgen receptor pathway or taxane chemotherapies have been used to treat CRPC patients leading to an increase in overall survival, but the occurrence of resistances limits their benefits. Numerous studies have demonstrated the implication of extracellular vesicles (EVs) in different cancer cellular mechanisms. Thus, the possibility to isolate and explore EVs produced by tumor cells in plasma/sera represents an important opportunity for the deciphering of those mechanisms and the discovery of biomarkers. Herein, we summarized the role of EVs in therapeutic resistance of advanced prostate cancer and their use to find biomarkers able to predict these resistances.
4 citations
TL;DR: A systematic review of EV biomarkers in PCa found mainly molecules with prognostic significance, molecules with diagnostic relevance, and molecules that serve both purposes to be the most investigated and proposed as potential tools to diagnose or predict resistance/sensitivity to advanced PCa treatments.
2 citations
References
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TL;DR: The GLOBOCAN series of the International Agency for Research on Cancer (IARC) as mentioned in this paper provides estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012.
Abstract: Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large “areas” of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths).
24,414 citations
TL;DR: When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plusprednisone.
Abstract: As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P = 0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel. conclusions When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.
5,264 citations
Université Paris-Saclay1, Cross Cancer Institute2, University of British Columbia3, Nevada Cancer Institute4, Université de Montréal5, Cardiff University6, University of Colorado Denver7, Baylor University Medical Center8, University of Calgary9, Sarah Cannon Research Institute10, University of California, San Francisco11, Memorial Sloan Kettering Cancer Center12
TL;DR: The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy.
Abstract: BACKGROUND Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy. METHODS We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate. RESULTS After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group. CONCLUSIONS The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.)
3,875 citations
TL;DR: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy, and was shown with respect to all secondary end points.
Abstract: Background Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor–signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy. Methods In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival. Results The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for de...
3,866 citations
University of Helsinki1, Semmelweis University2, Hungarian Academy of Sciences3, University of Szeged4, University of Palermo5, Institute of Molecular Pathology and Immunology of the University of Porto6, University of Porto7, Autonomous University of Barcelona8, Instituto de Biologia Molecular e Celular9, Ikerbasque10, Harvard University11, University of Duisburg-Essen12, Salk Institute for Biological Studies13, Paracelsus Private Medical University of Salzburg14, University of Colorado Denver15, Bilkent University16, Middle East Technical University17, University of Southern Denmark18, Statens Serum Institut19, Ghent University Hospital20, Oslo University Hospital21, University of Belgrade22, University of Ljubljana23, University of Mainz24, Finnish Red Cross25, University of Gothenburg26, Latvian Biomedical Research and Study centre27, University of Applied Sciences and Arts Northwestern Switzerland FHNW28, University of Valencia29, Centro Nacional de Investigaciones Cardiovasculares30, University of Freiburg31, Utrecht University32, Trinity College, Dublin33, Catalan Institution for Research and Advanced Studies34, University of Barcelona35, International University Of Catalonia36, Aarhus University Hospital37
TL;DR: A comprehensive overview of the current understanding of the physiological roles of EVs is provided, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia.
Abstract: In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.
3,690 citations