In order to proliferate in unfavourable conditions, cancer cells can take advantage of the naturally occurring endoplasmic reticulum-associated unfolded protein response (UPR) via three highly conserved signalling arms: IRE1α, PERK and ATF6. All three arms of the UPR have key roles in every step of tumour progression: from cancer initiation to tumour growth, invasion, metastasis and resistance to therapy. At present, no cure for metastatic prostate cancer exists, as targeting the androgen receptor eventually results in treatment resistance. New research has uncovered an important role for the UPR in prostate cancer tumorigenesis and crosstalk between the UPR and androgen receptor signalling pathways. With an improved understanding of the mechanisms by which cancer cells exploit the endoplasmic reticulum stress response, targetable points of vulnerability can be uncovered.
The endoplasmic reticulum (ER) detects cell stress and triggers the unfolded protein response (UPR) via three signalling arms: IRE1α, PERK and ATF6, leading to the transcription and translation of prosurvival response machinery.
Cancer cells hijack the UPR to thrive in unfavourable conditions, drive angiogenesis, evade immune surveillance, invade and migrate, initiate dormancy, grow from micrometastasis and develop resistance to treatment.
Prostate cancer cells overexpress chaperones (such as BiP) that translocate from the ER to the cell membrane to elicit cytoprotective effects in advanced prostate cancer.
Prostate cancer cells activate the IRE1α UPR arm via the androgen receptor (AR), and downstream XBP1s increases MYC expression, which ultimately leads to increased AR expression in a positive-feedback loop.
AR might downregulate PERK to decrease CHOP-mediated apoptosis, but in advanced prostate cancer, PERK signalling seems to be activated to avoid uncontrolled protein synthesis.
A number of molecules target ER homeostasis and show promising efficacy in vitro and in preclinical models of prostate cancer. Translational studies investigating these compounds will be required to bring them to clinical use.
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de la Calle, C.M., Shee, K., Yang, H. et al. The endoplasmic reticulum stress response in prostate cancer. Nat Rev Urol 19, 708–726 (2022). https://doi.org/10.1038/s41585-022-00649-3