scholarly journals Androgen Receptor-Induced Integrin α6β1 and Adhesion to Laminin Promotes Survival and Drug Resistance in Castration-Resistant Prostate Cancer through BNIP3

2018 ◽  
Author(s):  
Eric A. Nollet ◽  
Sourik S. Ganguly ◽  
Veronique V. Schulz ◽  
Anne Cress ◽  
Cindy K. Miranti
Keyword(s):  
Androgen Receptor ◽  
Tumor Cells ◽  
Castration Resistant Prostate Cancer ◽  
Bcl2 Family ◽  
Castration Resistant ◽  
Pi3k Inhibition ◽  
Survival Pathway ◽  
Prostate Cancers ◽  
Integrin Α6β1 ◽  
Resistant Cells

ABSTRACTAlthough castration-resistant prostate cancers no longer respond to anti-androgen therapies, the androgen receptor (AR) is still required to promote tumor survival. However, the signaling pathways downstream of AR that promote this survival are not well known. We recently identified an AR-dependent survival pathway whereby AR induction of integrin α6β1 and adhesion to laminin activates NF-kB/RelA signaling and Bcl-xL. This pathway acts in parallel with the PI3K/Akt pathway in Pten-null tumor cells such that combined inhibition of both PI3K and integrin α6β1 is required to kill tumor cells adherent to laminin. However, PTEN-null castration-resistant tumors were not effectively inhibited by this combination. We discovered that BNIP3, a hypoxia-induced BH3-only, pro-mitophagic Bcl2 family member, is induced by androgen in castration-resistant cells through integrin α6β1 signaling to HIF1α. Furthermore, castration-resistant cells adherent to laminin were much more efficient at inducing autophagy in response to androgen. Androgen blocked the ability of the PI3K inhibitor PX-866 to kill castration-resistant tumors, but this was reversed by loss of BNIP3. Although BNIP3 was dispensable for androgen-induced autophagy, its mitophagy function was required for BNIP3 to promote resistance to PI3K inhibition. Thus, adhesion to laminin triggers signaling through AR/α6β1/HIF1α in castration-resistant cells to drive the expression of BNIP3 and cooperates with AR/α6β1-mediated autophagy, both of which contribute to PI3K resistance through induction of mitophagy.

scholarly journals Global Gene Expression Characterization of Circulating Tumor Cells in Metastasic Castration-Resistant Prostate Cancer Patients

2020 ◽  
Vol 9 (7) ◽  
pp. 2066
Author(s):  
Luis León-Mateos ◽  
Alicia Abalo ◽  
Helena Casas ◽  
Urbano Anido ◽  
Óscar Rapado-González ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Global Gene Expression ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Viable Solution ◽  
Prostate Cancers ◽  
Expression Characterization

Background: Current therapeutic options in the course of metastatic castration-resistant prostate cancers (mCRPC) reinforce the need for reliable tools to characterize the tumor in a dynamic way. Circulating tumor cells (CTCs) have emerged as a viable solution to the problem, whereby patients with a variety of solid tumors, including PC, often do not have recent tumor tissue available for analysis. The biomarker characterization in CTCs could provide insights into the current state of the disease and an overall picture of the intra-tumor heterogeneity. Methods: in the present study, we applied a global gene expression characterization of the CTC population from mCRPC (n = 9), with the goal to better understand the biology of these cells and identify the relevant molecules favoring this tumor progression. Results: This analysis allowed the identification of 50 genes specifically expressed in CTCs from patients. Six of these markers (HOXB13, QKI, MAOA, MOSPD1, SDK1, and FGD4), were validated in a cohort of 28 mCRPC, showing clinical interest for the management of these patients. Of note, the activity of this CTC signature was related to the regulation of MYC, a gene strongly implicated in the biology of mCRPC. Conclusions: Overall, our results represent new evidence on the great value of CTCs as a non-invasive biopsy to characterize PC.

Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis

2005 ◽  
Vol 23 (32) ◽  
pp. 8253-8261 ◽  
Author(s):  
Howard I. Scher ◽  
Charles L. Sawyers
Keyword(s):  
Androgen Receptor ◽  
Receptor Activation ◽  
Castration Resistant Prostate Cancer ◽  
Activating Mutations ◽  
Resistant Disease ◽  
Castration Resistant ◽  
Signaling Axis ◽  
Hormone Refractory ◽  
Prostate Cancers ◽  
And Function

Prostate cancers that are progressing on medical and surgical therapies designed to ablate the action of androgens continue to express androgen receptor (AR) and to depend on signaling through the receptor for growth. A more clinically relevant classification of castration-resistant disease focuses on the mechanisms of receptor activation, which include (1) changes in the level of ligand(s) in tumor tissue; (2) increased levels of the protein due to gene amplification or altered mRNA expression; (3) activating mutations in the receptor that affect structure and function; (4) changes in coregulatory molecules including coactivators and corepressors; and (5) factors that lead to activation of the receptor independent of the level of ligand or receptor allowing kinase cross talk. From an AR perspective, the term “hormone refractory” is inappropriate. On the basis of this schema, we discuss strategies that are focused on the AR either directly or indirectly, as single agents or in combination, that are in clinical development.

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