CCN3-EZH2-AR feedback loop: new targets for enzalutamide and castration resistant prostate cancer
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You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III (PD59)1 Apr 2020PD59-11 TARGETING BCL2 TO INCREASE ENZALUTAMIDE SENSITIVITY TO BETTER SUPPRESS PROSTATE CANCER PROGRESSION THROUGH ALTERING ARV7 PROTEIN DEGRADATION Hua Xu* Hua Xu*Hua Xu* More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000969.011AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Androgen deprivation therapy (ADT) with antiandrogens targeting androgens/androgen receptor (AR) signaling is the standard used to treat prostate cancer in different clinical settings besides surgical treatment. However, most prostate cancer patients will eventually develop cancer progression despite castrate levels of testosterone, into castration resistant prostate cancer (CRPC). The recently developed antiandrogen, Enzalutamide, has reformed the standard of care for castration resistant prostate cancer patients. However, Enzalutamide resistance inevitably emerges despite success of Enzalutamide in prolonging castration resistant prostate cancer patients’ survival. Here we found that Enzalutamide resistant prostate cancer cells had higher BCL2 expression. We aimed to test whether targeting BCL2 would influence Enzalutamide sensitivity of prostate cancer and identify the potential mechanism. METHODS: The study was designed to target Enzalutamide induced BCL2 with inhibitor ABT263 and test Enzalutamide sensitivity in Enz-resistant prostate cancer cells by MTT assay. Cellular reactive oxygen species levels were detected with dihydroethidium staining, and in vitro deubiquitinating enzyme activity assay was used to evaluate ubiquitin specific protease 26 (USP26) activity. RESULTS: We retrospectively performed an RNA sequencing among 625 CRPC patients and 625 matched hormone-sensitive prostate cancer (HSPC) patients and revealed that BCL2 was significant increased in CRPC, which indicated that targeting BCL2 might be a potential option. BCL2 inhibitor, ABT263 could increase Enzalutamide sensitivity and increase the ubiquitination of androgen receptor (AR) and AR splice variant 7 (ARv7) and their ubiquitin/proteasome-dependent degradation in both Enzalutamide sensitive and Enzalutamide resistant prostate cancer cells. As BCL2 is a classical anti-apoptosis protein, we then tested the potential linkage of its anti-apoptotic activity to its ability to alter the AR and ARv7 expression. The results revealed that inhibition of BCL2 activity by ABT263 (with and without Enz treatment) resulted in cleaved-PARP expression in both EnzS1-C4-2 and EnzR1-C4-2 and EnzR3-CWR22Rv1 PCa cells, suggesting that ABT263 could promote PCa apoptosis. However, blocking apoptosis through inhibition of caspase activity with Z-VAD-FMK (pan-caspase inhibitor) failed to reverse the decrease of AR and ARv7 protein expression, suggesting that the apoptotic pathway was unlikely responsible for the decrease of AR and ARv7 expression. As BCL2 is a mitochondria protein that may alter the mitochondria function via modulating the ROS, we then tested weather ABT263 could function via altering the cellular ROS to decrease the AR and ARv7 expression to further influence Enzalutamide sensitivity. ABT263 treatment could significantly induce cellular ROS level in both EnzS1-C4-2 and EnzR1-C4-2 and EnzR3-CWR22Rv1 PCa cells. Elevated cellular reactive oxygen species levels might then inhibit USP26 activity to increase the ubiquitination of androgen receptor (AR) and AR splice variant 7 (ARv7) and their ubiquitin/proteasome-dependent degradation, which contributed to the increase of Enz sensitivity. In vivo mouse model also demonstrates that ABT263 will suppress the prostate cancer progression. CONCLUSIONS: This study demonstrated that targeting Enzalutamide induced BCL2 with inhibitor ABT263 could increase Enzalutamide sensitivity in both Enzalutamide sensitive and Enzalutamide resistant prostate cancer cells through induction of cellular reactive oxygen species levels and suppression of USP26 activity with a consequent increase of ubiquitin/proteasome-dependent degradation of AR and ARv7 protein expression. This preclinical study established the foundation to use ABT263 in combination with Enzalutamide to treat prostate cancer patients, especially those resistant to Enzalutamide. Source of Funding: National Natural Science Foundation of China (No. 81472377 and 81802570) © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1209-e1209 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hua Xu* More articles by this author Expand All Advertisement PDF downloadLoading ...
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The prevalence of prostate cancer continues to increase worldwide. The effectiveness of androgen deprivation therapy for advanced prostate cancer has a time limit, after which castration resistance and disease progression are formed. A part of patients with castrate-resistant prostate cancer has no metastases (according to standard imaging methods). The main goal of treatment of these patients is to prolong the time before metastasis formation. This article presents a review of the current understanding of the molecular mechanisms underlying the inhibition of androgen-receptor signaling with enzalutamide, a second-generation androgen receptor antagonist, and the results of clinical studies of its efficacy and safety in castrate-resistant prostate cancer without metastases. It was determined that enzalutamide stimulates the expression of a new class of genes that are not regulated by dihydrotestosterone. It was found that, in addition to inhibiting androgen receptors, enzalutamide can act as a partial transcriptional agonist. Enzalutamide therapy has been shown to reduce the risk of tumor progression and death in patients with non-metastatic castrate-resistant prostate cancer and is well tolerated. Treatment with this drug increases the time before metastases appear, before the first use of subsequent anti-tumor therapy is necessary, and the period before prostate-specific antigen levels have progressed. Study of mechanisms induced by enzalutamide – inhibition of prostate cancer cells growth and activation of genes contributing to cancer development by enzalutamide-related androgen receptor – can help to clarify possible ways of resistance formation to this drug and possibilities of its overcoming with combined therapy.
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Prostate cancer initially responds to androgen-deprivation therapy, but most patients eventually develop a castration-resistant form of disease. Enzalutamid is the superselective inhibitor of the androgen receptor (AR), which blocks several stages of the AR signal path. The drug showed significant effectiveness in the treatment of metastatic castration-resistant prostate cancer (MCRPC) in both the first line therapy and the second line therapy after the previous cytotoxic therapy of Docetaxel. To ensure optimum treatment, it is important to understand the impact of Enzalutamide in the context of other therapies, as recent studies have shown that cross-resistance occurs between and within classes of drugs. Mutations and AR splice-variants also affect prostate cancer. Future treatment strategies, including enzalutamide, should take into account the previous level of exposure to taxanes or anti-androgen therapy and the existence of variants of AR that may affect efficiency.
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Purpose: Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.Experimental Design: The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the in vivo effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.Results: High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.Conclusions: Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. Clin Cancer Res; 24(3); 708-23. ©2017 AACR.
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Enzalutamide (MDV3100) is a potent second-generation androgen receptor antagonist approved for the treatment of castration-resistant prostate cancer (CRPC) in chemotherapy-naïve as well as in patients previously exposed to chemotherapy. However, resistance to enzalutamide and enzalutamide withdrawal syndrome have been reported. Thus, reliable and integrated preclinical models are required to elucidate the mechanisms of resistance and to assess therapeutic settings that may delay or prevent the onset of resistance. In this study, the prostate cancer multistage murine model TRAMP and TRAMP-derived cells have been used to extensively characterize in vitro and in vivo the response and resistance to enzalutamide. The therapeutic profile as well as the resistance onset were characterized and a multiscale stochastic mathematical model was proposed to link the in vitro and in vivo evolution of prostate cancer. The model showed that all therapeutic strategies that use enzalutamide result in the onset of resistance. The model also showed that combination therapies can delay the onset of resistance to enzalutamide, and in the best scenario, can eliminate the disease. These results set the basis for the exploitation of this "TRAMP-based platform" to test novel therapeutic approaches and build further mathematical models of combination therapies to treat prostate cancer and CRPC.Significance: Merging mathematical modeling with experimental data, this study presents the "TRAMP-based platform" as a novel experimental tool to study the in vitro and in vivo evolution of prostate cancer resistance to enzalutamide.
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Ziel/Aim There is preliminary evidence for prostate-specific membrane antigen (PSMA) upregulation effects of androgen receptor blockade in prostate cancer. In an attempt to find the best condition for PSMA radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC) patients, we evaluated the effect of oral enzalutamide in each individual.
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Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.
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