The PERK/Akt Pathway Mediates Apoptosis Resistance to ER Ca2+ Stress in LNCaP Prostate Cancer Cells

Selective and targeted sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors represent a promising and new class of cancer chemotherapeutics that are under investigation in different clinical trials. However, resistance to cancer chemotherapeutics treatments is a common phenomenon and recent evidence suggests that SERCA inhibition could also lead to innate and/or acquired ability of cancer cells to evade cell death but the molecular mechanisms are not fully elucidated. In LNCaP prostate cancer cells, we discovered that activation of the PERK branch of the unfolded protein response (UPR) pathways is involved in therapeutic escape of the endoplasmic reticulum (ER)-Ca2+ stress inducer ASP-8ADT, the active compound of Mispsagargin. We show that the activation of the Akt pathway in response to UPR allows the survival of LNCaP cells to ASP- 8ADT exposure. Interestingly, pharmacological inhibition of the PERK downstream factors GSK-3β or eIF2α by drugs currently used in clinic greatly sensitizes LNCaP cells to ASP-8ADT. In summary, our findings highlight additional strategies to increase clinical response to targeting-ERCa2+ stressor drugs such as Mipsagargin family.