The ability of
capsaicin co-treatment to sensitize
cancer cells to anticancer drugs has been widely documented, but the detailed underlying mechanisms remain unknown. In addition, the role of
ribophorin II turnover on chemosensitization is still uncertain. Here, we investigated
capsaicin-induced sensitization to chemotherapeutic agents in the human oral
squamous carcinoma cell lines, HSC-3 and SAS. We found that
capsaicin (200 μM) did not induce remarkable apoptotic cell death in these cell lines; instead, it significantly enhanced autophagy with a concomitant decrease of
ribophorin II protein. This
capsaicin-induced decrease in
ribophorin II was intensified by the autophagy inducer,
rapamycin, but attenuated by the autophagy inhibitors, ULK1 inhibitor and
chloroquine, indicating that the autophagic process was responsible for the
capsaicin-induced down-regulation of
ribophorin II. Co-administration of
capsaicin with conventional
anticancer agents did, indeed, sensitize the
cancer cells to these agents. In co-treated cells, the induction of apoptosis was significantly reduced and the levels of the necroptosis markers, phospho-MLKL and phospho-RIP3, were increased relative to the levels seen in
capsaicin treatment alone. The levels of DNA damage response markers were also diminished by co-treatment. Collectively, our results reveal a novel mechanism by which
capsaicin sensitizes
oral cancer cells to anticancer drugs through the up-regulation of autophagy and down-regulation of
ribophorin II, and further indicate that the induction of necroptosis is a critical factor in the
capsaicin-mediated chemosensitization of oral
squamous carcinoma cells to conventional anticancer drugs.