Tunicamycin induces ER stress and inhibits tumorigenesis of head and neck cancer cells by inhibiting N-glycosylation.

Glycosylation plays an important role in the genesis of various cancers. The inhibition of glycosylation disturbs the protein folding machinery, causing the accumulation of unfolded proteins in the cell endoplasmic reticulum (ER) and inducing ER stress. Tunicamycin (TM) is an inhibitor of glycosylation that has shown marked antitumor activity. In this study, we investigated the effect of TM on the tumorigenesis of head and neck cancer cells. The effects of TM on cell proliferation, colony formation and tumorsphere formation in vitro and tumorigenicity in vivo were investigated in head and neck cancer cells. ER stress was determined by the evaluation of PERK, PDI, IRE1-alpha, BIP, Ero1-Lalpha and calnexin expression using western blotting and immunofluorescence. We found that TM inhibited colony formation and tumorsphere formation of head and neck cancer cells in vitro and suppressed tumor growth in vivo. After incubation with TM, the expression of the cancer stem cell markers CD44 and Bmi-1 was reduced, and the expression of the ER stress markers BIP, Ero1-Lalpha and calnexin was elevated. Moreover, the EGFR signaling pathway was inhibited, and nonglycosylated EGFR degradation was accelerated with TM treatment. Our results suggest that inhibition of glycosylation by TM may be a novel treatment strategy for use with HNSCC patients.