Osthole Exerts Inhibitory Effects on Hypoxic Colon Cancer Cells via EIF2α Phosphorylation-mediated Apoptosis and Regulation of HIF-1α

Hypoxic microenvironment and dysregulated endoplasmic reticulum stress/ unfolded protein response (UPR) system are considered important factors that promote cancer progression. Although osthole extracted from Cnidium monnieri (Fructus Cnidii) has been confirmed to exhibit an anticancer activity in various cancers, the effects of osthole in hypoxic colon cancer cells have not been explored. Therefore, the aim of this study was to examine whether osthole has an inhibitory effect on hypoxic colon cancer HCT116 cells and further investigate the underlying molecular mechanisms. Treatment with osthole significantly attenuated the cell viability, proliferation, and migration in hypoxic HCT116 cells. Osthole also activated UPR signaling such as phospho-eukaryotic initiation factor 2 alpha (EIF2 alpha)/ATF4/CHOP/DR5 cascade accompanied by upregulation of pro-apoptotic proteins. Moreover, the tubule-like formation of human umbilical vein endothelial cells, the secretion of vascular endothelial growth factor A, and the expression and activity of hypoxia-inducible factor-la (HIF-1 alpha) in hypoxic HCT116 cells were markedly suppressed by osthole. However, suppressing EIF2 alpha phosphorylation with salubrinal or ISRIB markedly reversed the effects of osthole on the expressions of pro-apoptotic proteins and HIF-1 alpha. Co-treatment of hypoxic HCT116 cells with osthole greatly increased the sensitivity to cisplatin and the expressions of phospho-EIF2 alpha and cleaved caspase 3. Collectively, the inhibitory effect of osthole in hypoxic HCT116 cells may be associated with EIF2 alpha phosphorylation-mediated apoptosis and translational repression of HIF-1 alpha. Taken together, osthole may be a potential agent in the treatment of colon cancer.

Automated summary

Osthole exhibits inhibitory effects on hypoxic colon cancer cells by activating the UPR signaling pathway and inducing apoptosis.