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

International audienceSelective 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 ASP8ADT 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

NALCN ‐mediated sodium influx confers metastatic prostate cancer cell invasiveness

International audienceThere is growing evidence that ion channels are critically involved in cancer cell invasiveness and metastasis. However, the molecular mechanisms of ion signaling promoting cancer behavior are poorly understood and the complexity of the underlying remodeling during metastasis remains to be explored. Here, using a variety of in vitro and in vivo techniques, we show that metastatic prostate cancer cells acquire a specific Na+ /Ca2+ signature required for persistent invasion. We identify the Na+ leak channel, NALCN, which is overexpressed in metastatic prostate cancer, as a major initiator and regulator of Ca2+ oscillations required for invadopodia formation. Indeed, NALCN-mediated Na+ influx into cancer cells maintains intracellular Ca2+ oscillations via a specific chain of ion transport proteins including plasmalemmal and mitochondrial Na+ /Ca2+ exchangers, SERCA and store-operated channels. This signaling cascade promotes activity of the NACLN-colocalized proto-oncogene Src kinase, actin remodeling and secretion of proteolytic enzymes, thus increasing cancer cell invasive potential and metastatic lesions in vivo. Overall, our findings provide new insights into an ion signaling pathway specific for metastatic cells where NALCN acts as persistent invasion controller