Inhibition of hypoxia‐induced HIF‐1α‐mediated autophagy enhances the in vitro antitumor activity of rhein in pancreatic cancer cells

A hypoxic microenvironment results in significantly elevated hypoxia‐inducible factor‐1 (HIF‐1) level in pancreatic cancer. HIF‐1 functions to maintain the survival of cancer cells. The present study was performed to investigate whether inhibition of HIF‐1α expression was involved in the in vitro antitumor effect of rhein in pancreatic cancer cells and to explore the underlying mechanism. sh‐RNA knockout technique and western blotting were used to investigate the role of HIF‐1α in autophagy activation in MiaPaCa‐2 and PANC‐1 cells. The survival and glycolysis were assessed using MTT assay and colorimetric kits, respectively. Apoptosis was evaluated by detecting the levels of apoptosis‐related proteins using western blotting. Among the five pancreatic cancer cell lines, MiaPaCa‐2 and PANC‐1 cells were more sensitive to hypoxia‐induced autophagy. HIF‐1α regulated hypoxia‐induced autophagy in MiaPaCa‐2 and PANC‐1 cells. Treatment with rhein inhibited the survival and suppressed glycolysis in MiaPaCa‐2 and PANC‐1 cells exposed to hypoxia. Bafilomycin A1 enhanced the suppressive effects of rhein on cell survival and glycolysis under hypoxia. Treatment with rhein, but not bafilomycin A1, significantly reduced HIF‐1α expression. In conclusion, inhibition of HIF‐1α‐mediated autophagy enhances the in vitro antitumor activity of rhein in pancreatic cancer cells under hypoxia. The present study was performed to investigate whether inhibition of HIF‐1α expression was involved in the antitumor effect of rhein in pancreatic cancer cells and to explore the underlying mechanism. We found that inhibition of HIF‐1α‐mediated autophagy enhanced the in vitro antitumor activity of rhein in pancreatic cancer cells under hypoxia.