The very unfavorable microenvironment of solid tumors with low pH, low oxygen tension, and deficient nutrient supply, as well as oncoprotein action, results in accumulation of misfolded proteins and metabolic disturbances that can signal cell death. Cancer cells have developed the capacity to survive these adverse conditions through precise modulation or ‘hijacking’ of stress pathways in the normal physiology. One central stress signaling pathway that is important in normal physiology and is also involved in disease states is endoplasmic reticulum (ER) stress. When there is undue stress on the normal cell, ER stress protective pathways, collectively termed the Unfolded Protein Response (UPR), are activated to maintain cellular homeostasis. When the chronic ER stress cannot be resolved, UPR instead activates cell death pathways. The cancer cell uses the cytoprotective aspects of the UPR for survival and skilfully steers the ‘double-edged sword’ of UPR. the ‘double-edged sword’ of UPR.
We recently showed that canonical UPR pathways are directly regulated by androgen receptor (AR) signaling in PCa cells and are critical for tumor survival and growth. We found that AR activated the inositol requiring enzme 1 alpha (IRE1α) pathway by directly increasing IRE1α gene expression as well as those of IRE1α target X-Box Protein 1S (XBP-1S, a major UPR transcription factor) target genes. Consistently, there is strong concordance between AR expression and IRE1α pathway mRNA gene expression in multiple large cohorts of human prostate cancer (PCa), including in CRPC. Furthermore, genetic targeting of IRE1α or XBP-1S, or small molecule (MKC8866) targeting of IRE1α, strongly inhibited PCa cell growth in vivo. We have shown that at least part of the mechanism of this is by direct activation of the oncogene c-MYC expression. MKC8866 is now in a Phase 1 Clinical Trial.
We have also found that one of the other canonical UPR pathways, protein kinase R-like endoplasmic reticulum kinase (PERK) – Activating Transcription Factor 4 (ATF4) pathway, is regulated by AR signaling and has important roles in PCa growth in vitro and in vivoWe have also found that one of the other canonical UPR pathways, protein kinase R-like endoplasmic reticulum kinase (PERK) – Activating Transcription Factor 4 (ATF4) pathway, is regulated by AR signaling and has important roles in PCa growth in vitro and in vivo. We have identified a number of novel ATF4 targets and have shown that they have an important role in PCa cell biology in vitro and in vivo. For example, we have found that mitochondrial one carbon (m1C) cycle gene expression is activated by ATF4 in PCa cells. This work has shown that components of the m1C cycle genes may serve as biomarkers or therapeutic targets. In another example, we have shown that the ATF4 target FAM129A can serve as a feedback regulator of the PERK-ATF4 signaling pathway by divergent effects at different levels. Our work is helping to provide the details of how UPR is functioning in normal cells and how it may be affected to support PCa growth and progression.
We are currently functionally dissecting the molecular basis of these pathways by genome wide knockout screens followed by molecular and cell biological characterization, as well as through generation of novel reporter cells. This work is exploring the possibility that important nodes of UPR may serve as biomarkers or therapeutic targets and thus have translational implications towards the clinic.