Deregulation of HSF1-mediated endoplasmic reticulum unfolded protein response promotes cisplatin resistance in lung cancer cells.

Mild hypothermia can induce apoptotic cell death in many cancer cells, but the underlying mechanisms remain unclear. In a genetic screen in Caenorhabditis elegans, we found that impaired endoplasmic reticulum unfolded protein response (UPR ER ) increased animal survival after cold shock. Consistently, in normal human lung cells, decreasing culture temperature from 37 to 30 °C activated UPR ER and promoted cell death. However, lung adenocarcinoma cells were impaired in UPR ER induction and resistant to hypothermia-induced cell death. Mechanistically, hypothermic stress increased HSF1 levels, which in turn activated UPR ER to promote apoptotic cell death. HSF1 expression was associated with UPR ER genes in normal tissues, but such association was lost in many cancers, especially lung adenocarcinoma. Activating UPR ER enhanced the cytotoxicity of chemotherapy drugs cisplatin preferentially in cancer cells. Consistently, cancer patients with higher UPR ER expression had generally better prognosis. Together, our study on hypothermia has led to the discovery of HSF1-UPR ER in the regulation of drug sensitivity in lung cancer cells, providing novel thoughts on developing new strategies against chemoresistance.