New Paradigms in Microtubule-Mediated Endocrine Signaling in Prostate Cancer

Abstract

Metastatic prostate cancer has limited therapeutic options and has remained a major clinical challenge. Historically, prostate cancer has been widely recognized as a chemotherapy-resistant disease. However, clinical studies with anti-microtubule agents over the past decade have shown important efficacy in improving survival in patients with advanced disease. The favorable outcomes with microtubule-targeted agents have thus rekindled interest in such therapies for the clinical management of prostate cancer. Microtubules are dynamic polymers of tubulin molecules that play diverse roles within the cell. The dynamic property of microtubules is responsible for forming the bipolar mitotic apparatus, the mitotic spindle, that functions to precisely segregate the chromosomes during cell division. Thus, owing to the pivotal role that they play in the orchestration of mitotic events, microtubules provide excellent targets for anti-cancer therapy. Recent evidence also suggests that microtubules play a crucial role in the regulation of endocrine signaling pathways. Interestingly, microtubule-targeted agents such as taxanes not only inhibit cell division but also impair endocrine receptor signaling in prostate cancer. Herein, we provide an overview of the current status of microtubule-targeted therapies that are used in the treatment of prostate cancer and discuss novel mechanisms by which such therapies modulate endocrine signaling in prostate cancer. We also address the emerging roles of microtubule regulatory proteins in prostate carcinogenesis that could serve as attractive targets for prostate cancer therapy and might also serve as predictive biomarkers to identify patients who may benefit from endocrine and/or chemotherapy. This may have important implications in designing mechanism-based and targeted-therapeutic strategies for prostate cancer. Mol Cancer Ther; 12(5); 555-66. Ó2013 AACR.

Multinucleation and Mesenchymal-to-Epithelial Transition Alleviate Resistance to Combined Cabazitaxel and Antiandrogen Therapy in Advanced Prostate Cancer

“…Thus PC3 AR v567es (androgen independent) and VCaP (androgen responsive) cells exhibited comparable degree of resistance to Cabazitaxel treatment, in accord with recent evidence that the antitumor effect of Cabazitaxel proceeds via an AR-independent mechanism (38). The mechanisms driving therapeutic cross-resistance to taxanes and antiandrogens in CRPC involve microtubule stabilization and inhibition of AR activity and nuclear localization by interfering with tubulin-AR association (16-18). Compelling evidence identified new signaling effectors conferring mechanistic resistance to taxane chemotherapy in CRPC, including overexpression of ERG genes (39) and activation of the GATA2-IGF2 signaling axis (40).…”

“…Work by our group and others established that Docetaxel chemotherapy inhibits AR trafficking and nuclear translocation, thus preventing its transcriptional activity (15-17). Taxanes also upregulate Forkhead box 01 (FOXO1), a transcriptional repressor of AR, resulting in inhibition of ligand-dependent and -independent transcription, and downregulation of AR and PSA expression (18,19). …”

“…The therapeutic impact of taxanes in metastatic CRPC and improving patient survival, has been attributed to microtubule stabilization and AR targeting ADT (18,20). Despite an initial efficacy and a survival advantage in patients with mCRPC, resistance to taxane chemotherapy invariably develops leading to disease progression (21).…”

Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

“…Emerging evidence suggests that taxanes such as docetaxel and cabazitaxel inhibit AR mediated gene expression 118119. Intact microtubule function is required for translocation of the AR to the nucleus, with taxanes causing accumulation of cytoplasmic AR 120121.…”

RNase L Suppresses Androgen Receptor Signaling, Cell Migration and Matrix Metalloproteinase Activity in Prostate Cancer Cells

“…We have not ruled out the possibility that RNase L may alter AR interaction with HSP proteins. However, given that RNase L has been shown to regulate actin dynamics [3], interact with ECM and cytoskeletal proteins [24,26] and, importantly, inhibition of microtubule and cytoskeletal dynamics inhibits androgen-dependent AR nuclear translocation and AR transcriptional activity [30,31,57,58]; together these data suggest significant involvement of RNase L-regulated actin dynamics in AR translocation.…”