Stress signaling pathways and prostate cancer
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 skillfully steers the ‘double-edged sword’ of UPR.
We recently showed that canonical UPR pathways are directly regulated by AR signaling in PCa cells and are critical for tumor survival and growth. We found that AR activated the inositol requiring enzyme 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 PCa, including in CRPC. Furthermore, genetic targeting of IRE1α or XBP-1S, or small molecule targeting of IRE1α strongly inhibited PCa cell growth in vivo. 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 vivo.
We are currently functionally dissecting the molecular basis of these pathways and exploring the possibility that their genetic or small molecule inhibition may have translational implications for the clinic.