miR‐103a‐2‐5p/miR‐30c‐1‐3p inhibits the progression of prostate cancer resistance to androgen ablation therapy via targeting androgen receptor variant 7

2019 ◽  
Vol 120 (8) ◽  
pp. 14055-14064 ◽  
Author(s):  
Wenjie Chen ◽  
Gan Yao ◽  
Keqin Zhou
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Resistance ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Androgen Ablation Therapy

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.

scholarly journals Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2653
Author(s):  
Gaetano Aurilio ◽  
Alessia Cimadamore ◽  
Roberta Mazzucchelli ◽  
Antonio Lopez-Beltran ◽  
Elena Verri ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Treatment Resistance ◽  
Resistance Mechanisms ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Castration Resistant ◽  
Receptor Signaling Pathway ◽  
Serum Androgens ◽  
Androgen Ablation Therapy

Around 80–90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient’s response to androgen ablation therapy is variable, and 20–30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.

scholarly journals Crosstalk Between Nuclear MET and SOX9/β-Catenin Correlates with Castration-Resistant Prostate Cancer

2014 ◽  
Vol 28 (10) ◽  
pp. 1629-1639 ◽  
Author(s):  
Yingqiu Xie ◽  
Wenfu Lu ◽  
Shenji Liu ◽  
Qing Yang ◽  
Brett S. Carver ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Combined Treatment ◽  
Castration Resistant Prostate Cancer ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Castration Resistant ◽  
Activate Cell ◽  
Androgen Ablation Therapy

Castration-resistant prostate cancer (PCa) (CRPC) is relapse after various forms of androgen ablation therapy and causes a major mortality in PCa patients, yet the mechanism remains poorly understood. Here, we report the nuclear form of mesenchymal epithelial transition factor (nMET) is essential for CRPC. Specifically, nMET is remarkably increased in human CRPC samples compared with naïve samples. Androgen deprivation induces endogenous nMET and promotes cell proliferation and stem-like cell self-renewal in androgen-nonresponsive PCa cells. Mechanistically, nMET activates SRY (sex determining region Y)-box9, β-catenin, and Nanog homeobox and promotes sphere formation in the absence of androgen stimulus. Combined treatment of MET and β-catenin enhances the inhibition of PCa cell growth. Importantly, MET accumulation is detected in nucleus of recurrent prostate tumors of castrated Pten/Trp53 null mice, whereas MET elevation is predominantly found in membrane of naïve tumors. Our findings reveal for the first time an essential role of nMET association with SOX9/β-catenin in CRPC in vitro and in vivo, highlighting that nuclear RTK activate cell reprogramming to drive recurrence, and targeting nMET would be a new avenue to treat recurrent cancers.

Molecular Biology Underlying the Clinical Heterogeneity of Prostate Cancer: An Update

2009 ◽  
Vol 133 (7) ◽  
pp. 1033-1040 ◽  
Author(s):  
A. Craig Mackinnon ◽  
Benjamin C. Yan ◽  
Loren J. Joseph ◽  
Hikmat A. Al-Ahmadie
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Molecular Biology ◽  
Gene Rearrangement ◽  
Molecular Characteristics ◽  
Early Event ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Development Of Resistance ◽  
Prostate Cancers

Abstract Context.—Recent studies have uncovered a number of possible mechanisms by which prostate cancers can become resistant to systemic androgen deprivation, most involving androgen-independent reactivation of the androgen receptor. Genome-wide expression analysis with microarrays has identified a wide array of genes that are differentially expressed in metastatic prostate cancers compared to primary nonrecurrent tumors. Recently, recurrent gene fusions between TMPRSS2 and ETS family genes have been identified and extensively studied for their role in prostatic carcinoma. Objective.—To review the recent developments in the molecular biology of prostate cancer, including those pertaining to the androgen receptor and the newly identified TMPRSS2-related translocations. Data Sources.—Literature review and personal experience. Conclusions.—Prostatic adenocarcinoma is a heterogeneous group of neoplasms with a broad spectrum of pathologic and molecular characteristics and clinical behaviors. Numerous mechanisms contribute to the development of resistance to androgen ablation therapy, resulting in ligand-independent reactivation of the androgen receptor, including amplification, mutation, phosphorylation, and activation of coreceptors. Multiple translocations of members of the ETS oncogene family are present in approximately half of clinically localized prostate cancers. TMPRSS2:ERG gene rearrangement appears to be an early event in prostate cancer and is not observed in benign or hyperplastic prostatic epithelium. Duplication of TMPRSS2:ERG appears to predict a worse prognosis. The relationship between TMPRSS2:ERG gene rearrangement and other morphologic and prognostic parameters of prostate cancer is still unclear.

scholarly journals α-Actinin-4 Promotes the Progression of Prostate Cancer Through the Akt/GSK-3β/β-Catenin Signaling Pathway

2020 ◽  
Vol 8 ◽  
Author(s):  
Sungyeon Park ◽  
Minsoo Kang ◽  
Suhyun Kim ◽  
Hyoung-Tae An ◽  
Jan Gettemans ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Actin Binding ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Ablation Therapy ◽  
Androgen Ablation ◽  
Proliferation And Metastasis ◽  
Gsk 3Β ◽  
Androgen Ablation Therapy

The first-line treatment for prostate cancer (PCa) is androgen ablation therapy. However, prostate tumors generally recur and progress to androgen-independent PCa (AIPC) within 2–3 years. α-Actinin-4 (ACTN4) is an actin-binding protein that belongs to the spectrin gene superfamily and acts as an oncogene in various cancer types. Although ACTN4 is involved in tumorigenesis and the epithelial–mesenchymal transition of cervical cancer, the role of ACTN4 in PCa remains unknown. We found that the ACTN4 expression level increased during the transition from androgen-dependent PCa to AIPC. ACTN4 overexpression resulted in enhanced proliferation and motility of PCa cells. Increased β-catenin due to ACTN4 promoted the transcription of genes involved in proliferation and metastasis such as CCND1 and ZEB1. ACTN4-overexpressing androgen-sensitive PCa cells were able to grow in charcoal-stripped media. In contrast, ACTN4 knockdown using si-ACTN4 and ACTN4 nanobody suppressed the proliferation, migration, and invasion of AIPC cells. Results of the xenograft experiment revealed that the mice injected with LNCaPACTN4 cells exhibited an increase in tumor mass compared with those injected with LNCaPMock cells. These results indicate that ACTN4 is involved in AIPC transition and promotes the progression of PCa.

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