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 (UPRER) increased animal survival after cold shock. Consistently, in normal human lung cells, decreasing culture temperature from 37 to 30 degrees C activated UPRER and promoted cell death. However, lung adenocarcinoma cells were impaired in UPRER induction and resistant to hypothermia-induced cell death. Mechanistically, hypothermic stress increased HSF1 levels, which in turn activated UPRER to promote apoptotic cell death. HSF1 expression was associated with UPRER genes in normal tissues, but such association was lost in many cancers, especially lung adenocarcinoma. Activating UPRER enhanced the cytotoxicity of chemotherapy drugs cisplatin preferentially in cancer cells. Consistently, cancer patients with higher UPRER expression had generally better prognosis. Together, our study on hypothermia has led to the discovery of HSF1-UPRER in the regulation of drug sensitivity in lung cancer cells, providing novel thoughts on developing new strategies against chemoresistance.