scholarly journals Signaling Pathways That Control Apoptosis in Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 937
Author(s):  
Amaal Ali ◽  
George Kulik
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Receptor Activation ◽  
Castration Resistant Prostate Cancer ◽  
Paracrine Factors ◽  
Androgen Independence ◽  
Androgen Ablation ◽  
Prostate Epithelial Cells

Prostate cancer is the second most common malignancy and the fifth leading cancer-caused death in men worldwide. Therapies that target the androgen receptor axis induce apoptosis in normal prostates and provide temporary relief for advanced disease, yet prostate cancer that acquired androgen independence (so called castration-resistant prostate cancer, CRPC) invariably progresses to lethal disease. There is accumulating evidence that androgen receptor signaling do not regulate apoptosis and proliferation in prostate epithelial cells in a cell-autonomous fashion. Instead, androgen receptor activation in stroma compartments induces expression of unknown paracrine factors that maintain homeostasis of the prostate epithelium. This paradigm calls for new studies to identify paracrine factors and signaling pathways that control the survival of normal epithelial cells and to determine which apoptosis regulatory molecules are targeted by these pathways. This review summarizes the recent progress in understanding the mechanism of apoptosis induced by androgen ablation in prostate epithelial cells with emphasis on the roles of BCL-2 family proteins and “druggable” signaling pathways that control these proteins. A summary of the clinical trials of inhibitors of anti-apoptotic signaling pathways is also provided. Evidently, better knowledge of the apoptosis regulation in prostate epithelial cells is needed to understand mechanisms of androgen-independence and implement life-extending therapies for CRPC.

scholarly journals Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression

2016 ◽  
Vol 113 (22) ◽  
pp. 6259-6264 ◽  
Author(s):  
Kazumasa Komura ◽  
Seong Ho Jeong ◽  
Kunihiko Hinohara ◽  
Fangfang Qu ◽  
Xiaodong Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cell Lines ◽  
Eastern Cooperative Oncology Group ◽  
Receptor Activation ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Ablation ◽  
Docetaxel Resistance ◽  
Hormone Sensitive ◽  
Docetaxel Sensitivity

The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity.

scholarly journals Interplay Between SOX9, Wnt/β-Catenin and Androgen Receptor Signaling in Castration-Resistant Prostate Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2066 ◽  
Author(s):  
Namrata Khurana ◽  
Suresh C. Sikka
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Form Complex ◽  
Androgen Receptor Signaling ◽  
Castration Resistant ◽  
Signaling Axis

Androgen receptor (AR) signaling plays a key role not only in the initiation of prostate cancer (PCa) but also in its transition to aggressive and invasive castration-resistant prostate cancer (CRPC). However, the crosstalk of AR with other signaling pathways contributes significantly to the emergence and growth of CRPC. Wnt/β-catenin signaling facilitates ductal morphogenesis in fetal prostate and its anomalous expression has been linked with PCa. β-catenin has also been reported to form complex with AR and thus augment AR signaling in PCa. The transcription factor SOX9 has been shown to be the driving force of aggressive and invasive PCa cells and regulate AR expression in PCa cells. Furthermore, SOX9 has also been shown to propel PCa by the reactivation of Wnt/β-catenin signaling. In this review, we discuss the critical role of SOX9/AR/Wnt/β-catenin signaling axis in the development and progression of CRPC. The phytochemicals like sulforaphane and curcumin that can concurrently target SOX9, AR and Wnt/β-catenin signaling pathways in PCa may thus be beneficial in the chemoprevention of PCa.

MicroRNA Regulation of Androgen Receptor in Castration-Resistant Prostate Cancer: Premises, Promises, and Potentials

2020 ◽  
Vol 13 ◽  
Author(s):  
Safieh Ebrahimi ◽  
Seyed Isaac Hashemy ◽  
Amirhossein Sahebkar ◽  
Seyed Hamid AghaeeBakhtiari
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Signaling Pathways ◽  
Therapeutic Potential ◽  
Splice Variants ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Contributing Factors ◽  
Development Of Resistance ◽  
Castration Resistant

: Prostate cancer (PCa) is the second most prevalent cancer and the fifth leading cause of cancer-related deaths among men. Androgen deprivation therapy (ADT) is the most frequently used therapeutic strategy in PCa; however, the development of resistance to ADT, known as castration-resistant prostate cancer (CRPC), continues to be a major obstacle against successful treatment of PCa. The abnormal activation of the androgen receptor (AR) signaling pathway has been found as one of the main contributing factors to the development of resistance in CRPC. Therefore, AR regulatory strategies are urgently required to combat resistance. Recently, microRNAs (miRNAs) have been found as major AR regulatory factors affecting ADT resistance. MiRNAs can target AR itself, AR-related genes, AR splice variants, ARrelated signaling pathways as well as cancer stem cells (CSCs), and play critical roles in regulating ADT resistance. Due to their capability to affect various genes and signaling pathways, miRNAs are now being studied for their potential role as a new therapeutic target in CRPC. It has been recommended that combination therapies including miRNAs and existing drugs can synergistically decrease castration resistance. miRNAs have also prognostic values for ADT, and their expression profiling in CRPC patients before therapeutic scheduling may enable the physician to diagnose patients who are ADT-resistant. Overall, extant evidence obviously supports the predictive and therapeutic potential of miRNAs in CRPC patients. This review summarizes the available information about the microRNA-mediated AR controlling mechanisms involved in ADT resistance.

scholarly journals Testosterone, prolactin, and oncogenic regulation of the prostate gland. A new concept: Testosterone-independent malignancy is the development of prolactin-dependent malignancy!

2018 ◽  
Author(s):  
Leslie C. Costello ◽  
Renty B. Franklin
Keyword(s):  
Prostate Cancer ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Prostate Gland ◽  
Peripheral Zone ◽  
Metabolic Function ◽  
Androgen Ablation ◽  
Prolactin Signaling ◽  
Maintenance Metabolism

Hormone-independent malignancy is a major issue of morbidity and deaths that confronts prostate cancer. Despite decades of research, the oncogenic and hormonal implications in the development and progression of prostate malignancy remain mostly speculative. This is largely due to the absence and/or lack of consideration by contemporary clinicians and biomedical investigators regarding the established implications of the co-regulation of testosterone and prolactin in the development, maintenance, metabolism and functions of the prostate gland. Especially relevant is the major metabolic function of production of high levels of citrate by the peripheral zone acinar epithelial cells. Citrate production, along with growth and proliferation by these cells, is regulated by co-existing testosterone and prolactin signaling pathways; and by the oncogenic down-regulation of ZIP1 transporter/zinc/citrate in the development of malignancy. These relationships had not been considered in the issues of hormonedependent malignancy. This review provides the relevant background that has established the dual role of testosterone and prolactin regulation of the prostate gland; which is essential to address the implications in the oncogenic development and progression of hormone-dependent malignancy. The oncogenic factor along with testosterone-dependent and prolactin-dependent relationships leads to the plausible concept that androgen ablation for the treatment of testosterone-dependent malignancy results in the development of prolactin-dependent malignancy; which is testosterone-independent malignancy. Consequently, both testosterone ablation and prolactin ablation are required to prevent and/or abort terminal hormonedependent prostate cancer.

scholarly journals Mechanisms of Androgen Receptor Activation in Castration-Resistant Prostate Cancer

Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4010-4017 ◽  
Author(s):  
Nima Sharifi
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Systemic Treatment ◽  
Receptor Activation ◽  
Constitutive Activity ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Recent Developments ◽  
Steroid Receptor Coactivators ◽  
Androgen Receptor Activation

Systemic treatment of advanced prostate cancer is initiated with androgen deprivation therapy by gonadal testosterone depletion. Response durations are variable and tumors nearly always become resistant as castration-resistant prostate cancer (CRPC), which is driven, at least in part, by a continued dependence on the androgen receptor (AR). The proposed mechanisms that underlie AR function in this clinical setting are quite varied. These include intratumoral synthesis of androgens from inactive precursors, increased AR expression, AR activation through tyrosine kinase-dependent signaling, alterations in steroid receptor coactivators, and expression of a truncated AR with constitutive activity. Various pharmacologic interventions have clinically validated some of these mechanisms, such as those that require the AR ligand-binding domain. Clinical studies have failed to validate other mechanisms, and additional mechanisms have yet to be tested in patients with CRPC. Here, we review the mechanisms that elicit AR activity in CRPC, with a particular focus on recent developments.

scholarly journals Combinatorial androgen receptor targeted therapy for prostate cancer

2006 ◽  
Vol 13 (3) ◽  
pp. 653-666 ◽  
Author(s):  
P Singh ◽  
A Uzgare ◽  
I Litvinov ◽  
S R Denmeade ◽  
J T Isaacs
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Targeted Therapy ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Signaling Molecules ◽  
Signaling Cascade ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Androgen Ablation Therapy

Prostatic carcinogenesis is associated with changes in the androgen receptor (AR) axis converting it from a paracrine dependence upon stromal signaling to an autocrine-initiated signaling for proliferation and survival of prostatic cancer cells. This malignant conversion is due to gain of function changes in which the AR activates novel genomic (i.e. transcriptional) and non-genomic signaling pathways, which are not present in normal prostate epithelial cells. During further progression, additional molecular changes occur which allow these unique malignancy-dependent AR signaling pathways to be activated even in the low androgen ligand environment present following androgen ablation therapy. These signaling pathways are the result of partnering the AR with a series of other genomic (e.g. transcriptional co-activators) or non-genomic (e.g. steroid receptor co-activator (Src) kinase) signaling molecules. Thus, a combinatorial androgen receptor targeted therapy (termed CART therapy) inhibiting several points in the AR signaling cascade is needed to prevent the approximately 30,000 US males per year dying subsequent to failure of standard androgen ablation therapy. To develop such CART therapy, a series of agents targeted at specific points in the AR cascade should be used in combination with standard androgen ablative therapy to define the fewest number of agents needed to produce the maximal therapeutic anti-prostate cancer effect. As an initial approach for developing such CART therapy, a variety of new agents could be combined with luteinizing hormone-releasing hormone analogs. These include: (1) 5α-reductase inhibitors to inhibit the conversion of testosterone to the more potent androgen, dihydrotestosterone; (2) geldanamycin analogs to downregulate AR protein in prostate cancer cells, (3) ‘bulky’ steroid analogs, which can bind to AR and prevent its partnering with other co-activators/signaling molecules, and (4) small molecule kinase inhibitors to inhibit MEK, which is activated as part of the malignant AR signaling cascade.

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