HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer

Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1Ser616 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1Ser616 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.