Considerations for the use of gonadotropin‐releasing hormone agonists and antagonists in patients with prostate cancer

Poppel, Hendrik Van; Abrahamsson, Peter

doi:10.1111/iju.14303

Cited by 23 publications

(26 citation statements)

References 75 publications

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“…ADT is the standard indication for treating locally advanced and metastatic PCa, achieved primarily by GnRH (gonadotropin-releasing hormone) agonists ( 26 , 27 ), GnRH antagonists ( 28 , 29 ), and androgen receptor antagonistic agents ( 30 ). Currently, the most widely used anti-androgen drugs are bicalutamide, Abiraterone and Enzalutamide ( 4 ).…”

Section: Discussionmentioning

confidence: 99%

Enzalutamide-Induced Upregulation of PCAT6 Promotes Prostate Cancer Neuroendocrine Differentiation by Regulating miR-326/HNRNPA2B1 Axis

et al. 2021

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Our previous studies have demonstrated that Enzalutamide-induced upregulation of long non-coding RNA p21 (lncRNA-p21) facilitates prostate cancer (PCa) neuroendocrine differentiation (NED). Given the important role of lncRNAs in PCa pathogenesis, and given that lots of lncRNAs are dys-regulated in neuroendocrine PCa (NEPC) patients, we next explored the biological function and underlying mechanism of lncRNA-PCAT6 (PCAT6) in mediating Enzalutamide-induced NED. The level of PCAT6 in Enzalutamide-treated PCa cells and NEPC samples were assessed using quantitative RT-PCR (qPCR). The effect of PCAT6 on PCa cell proliferation, invasion, and NED was evaluated through CCK-8, transwell, qPCR, western blot analysis, Xenograft mouse model, and in vivo lung metastasis model. We found that PCAT6 was highly expressed in NE-like cells (PC3, DU145, and NCI-H660) compared with androgen-sensitive LNCaP cells. PCAT6 was also highly expressed in NEPC tissues. Enzalutamide treatment resulted in a significant increase of PCAT6 level in a dose- and time-dependent fashion. Functionally, PCAT6 overexpression promoted NED of C4-2 cells, as evidenced by an increased expression of NE markers (NSE, ChgA, and SYP), whereas PCAT6 knockdown in NCI-H661 cells repressed NED. Furthermore, PCAT6 overexpression promoted PCa cell proliferation and invasion in vitro and in vivo. Mechanistically, PCAT6 functioned as competing endogenous (ce) RNA via absorbing miR-326, thus resulting in a de-suppression of Hnrnpa2b1 target gene. The current results demonstrate that PCAT6 acted as a tumor activator in PCa progression by sponging miR-326 and increasing Hnrnpa2b1 expression and that the PCAT6/miR-326/Hnrnpa2b1 signaling might be a new therapeutic target for PCa.

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Section: Discussionmentioning

confidence: 99%

Enzalutamide-Induced Upregulation of PCAT6 Promotes Prostate Cancer Neuroendocrine Differentiation by Regulating miR-326/HNRNPA2B1 Axis

et al. 2021

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“…Metastatic prostate cancers are initially treated with androgen deprivation therapy (ADT) because prostate tissue (benign or malignant) expresses androgen receptor (AR) protein that is critical for prostate cancer development and progression ( 3 , 4 ). Castration by surgery or medical treatment reduces androgen hormones, resulting in prostatic atrophy and cancer regression ( 5 ).…”

Section: Androgen Deprivation and Anti-androgen Therapies In The Clinicmentioning

confidence: 99%

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Huang

Lin

2022

Front. Oncol.

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Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models via distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.

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“…These compounds act by competitively binding to the pituitary GnRH-Rs, thus immediately suppressing LH and FSH secretion; they were also reported to decrease FSH release for a longer time period and to lower levels than GnRH agonists [ 121 ]. Thus, GnRH agonists and antagonists still represent the standard ADT therapy for patients with metastatic PCa [ 122 , 123 , 124 ].…”

Section: The Gnrh/gnrh-r Axis In Crpcmentioning

confidence: 99%

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

Fontana

Limonta

2021

Cells

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Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.

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Considerations for the use of gonadotropin‐releasing hormone agonists and antagonists in patients with prostate cancer

Cited by 23 publications

References 75 publications

Enzalutamide-Induced Upregulation of PCAT6 Promotes Prostate Cancer Neuroendocrine Differentiation by Regulating miR-326/HNRNPA2B1 Axis

Enzalutamide-Induced Upregulation of PCAT6 Promotes Prostate Cancer Neuroendocrine Differentiation by Regulating miR-326/HNRNPA2B1 Axis

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

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