Androgens modulate autophagy and cell death via regulation of the endoplasmic reticulum chaperone glucose-regulated protein 78/BiP in prostate cancer cells

Abstract

Pro-survival signalling mediated by the androgen receptor (AR) is implicated as a key contributor to prostate carcinogenesis. As prostate tumours are characterized by nutrient-poor, hypoxic and acidified microenvironments, one mechanism whereby AR signalling may contribute to survival is by promoting adaptation to cellular stress. Here we have identified a novel role for AR in the inhibition of autophagy induced by serum withdrawal. This blockade is attributed to AR-mediated upregulation of the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78/BiP (Grp78/BiP), and occurs independently of ER stress response pathway activation. Interestingly, AR activation did not affect serum starvation-induced mammalian target of rapamycin inhibition, illustrating that the adaptive role for androgens lies not in the ability to modulate nutrient sensing, but in the promotion of ER stability. Finally, we show that the adaptive advantage conferred by AR-mediated Grp78/BiP upregulation is temporary, as upon chronic serum starvation, AR activation delayed but did not suppress the onset of autophagy and cell death. This study reveals a novel mechanism whereby maintained AR signalling promotes temporary adaptation to cellular stress and in turn may contribute to the evasion of prostate tumour cell death.

A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer

“…Despite initial indications of a functional role for autophagy in prostate cancer, it is still not clear how this process is used during the different stages of the disease or how it is regulated. For example, there are discrepancies regarding AR’s regulation of autophagy 30,242,243,245 . This is somewhat surprising given AR’s robust induction of AMPK in prostate cancer 33–36,130 .…”

Autophagy as a modulator and target in prostate cancer

“…[49] Unfortunately, advanced prostate cancer being treated with ADT ultimately progresses to a lethal phenotype known as castration-resistant prostate cancer. [50] Research conducted in our lab and elsewhere indicates that ADT stimulates autophagic activity – facilitating the development of the castration resistant phenotype.…”

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