Divergent androgen regulation of unfolded protein response pathways drives prostate cancer

Abstract

The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer (PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor (AR), which is critical for PCa survival. AR bound to gene regulatory sites and activated the IRE1α branch, but simultaneously inhibited PERK signaling. Inhibition of the IRE1α arm profoundly reduced PCa cell growth in vitro as well as tumor formation in preclinical models of PCa in vivo. Consistently, AR and UPR gene expression were correlated in human PCa, and spliced XBP-1 expression was significantly upregulated in cancer compared with normal prostate. These data establish a genetic switch orchestrated by AR that divergently regulates the UPR pathways and suggest that targeting IRE1α signaling may have therapeutic utility in PCa.

Anticipatory UPR Activation: A Protective Pathway and Target in Cancer

“…While the mitogens E 2 , EGF and VEGF and the small molecule BHPI all activate the rapid anticipatory UPR pathway, DHT does not [21]. Instead, DHT activates the UPR after many hours [22]. Supporting the proposed pathway, inhibition and knockdown of PLCγ blocks UPR activation by all four rapid activators [17–20].…”

Glycosylation is a global target for androgen control in prostate cancer cells

“…Our approach produced a comprehensive map of 700 genes controlled by the AR in clinical prostate cancer and provides a new window through which to understand the signalling pathways downstream of the AR . Gene set enrichment analysis of these 700 genes identified known AR-regulated processes including fatty acid metabolism (Swinnen et al 1997a, Liu 2006), response to endoplasmic reticulum stress (Segawa et al 2002, Sheng et al 2015 and cholesterol and lipid biosynthesis (Swinnen et al 1997b, Suburu & Chen 2012, Wu et al 2014, Butler et al 2016. In addition to these well-characterised AR-regulated pathways, our data highlighted 'glycosylation' as a previously unidentified global target for androgen control in prostate cancer cells .…”

Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action

“…Together, these data suggest DHT may activate the UPR through a reactive UPR mechanism, in which UPR activation is stimulated by accumulation of misfolded and unfolded proteins as the cells proliferate, or through a nuclear gene expression program that induces UPR-related mRNAs. Although the exact molecular mechanism underlying DHT activation of the UPR requires further exploration, pharmacological inhibition of IRE1α significantly reduces prostate tumor growth [33]. This supports the biological significance of activation of the UPR pathway in prostate cancer progression.…”

“…However, activation of the UPR was observed at later times (e.g. 24 to 48 hours) [33]. Together, these data suggest DHT may activate the UPR through a reactive UPR mechanism, in which UPR activation is stimulated by accumulation of misfolded and unfolded proteins as the cells proliferate, or through a nuclear gene expression program that induces UPR-related mRNAs.…”