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

H L Bennett,J O'Prey,J T Fleming,K M Ryan,H Y Leung

doi:10.1038/cddis.2010.50

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.

Highlights

One stimulus that can promote autophagy is endoplasmic reticulum (ER) stress
Serum starvation leads to the reduction of androgen receptor (AR) expression, mibolerone-treated cells exhibited protein levels of AR similar to that observed in cells maintained in fetal bovine serum (FBS) (Figure 1a)
We report the novel finding that in this context, androgen treatment does not inhibit autophagy by initiating Mammalian target of rapamycin (mTOR) signalling, but rather acts via upregulation of Grp78/BiP, a key mediator of ER stability

Summary

Introduction

One stimulus that can promote autophagy is endoplasmic reticulum (ER) stress. numerous signalling effectors have been implicated in linking these two processes, the precise molecular mechanisms remain elusive.[17,18,19,20] Inducers of ER stress such as nutrient starvation lead to the accumulation of unfolded proteins within the ER lumen.[21,22] Like autophagy, the ER stress response is initiated to minimize cellular insult, in this case by halting global translation, thereby reducing the protein overload within the ER.[23]. The accumulation of unfolded proteins titrates Grp78/BiP from binding to the luminal tails of the ER transmembrane proteins PRK-like ER kinase (PERK), inositolrequiring transmembrane kinase/endonuclease (IRE-1) and activating transcription factor 6 (ATF6) This allows for autophosphorylation of PERK, which in turn phosphorylates and inhibits eukaryotic initiation factor 2a (eIF2a). Long-term androgen treatment significantly delayed both the onset of autophagy and cell death compared with cells serum-starved without androgens and this delay in cell death was blocked by Grp78/BiP knockdown These results support a novel mechanism – modulation of autophagy by Grp78/BiP – by which AR signalling may promote adaptation to nutrient starvation and in turn evasion of cell death

Methods

Results

Conclusion