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

Abstract

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.

Rhein Induces Oral Cancer Cell Apoptosis and ROS via Suppresse AKT/mTOR Signaling Pathway In Vitro and In Vivo

“…Rhein is a natural anthraquinone found in several medicinal plants such as Rheum undulatum, Rheum palmatum, and Cassia reticulata [18] that exerts various pharmacological activities, including anti-inflammation, antioxidation, and anticancer activities [19,20]. Previous studies have confirmed that rhein is associated with autophagy in pancreatic cancer cells [21]. Previous studies have suggested that rhein suppressed non-small-cell lung cancer cell growth in vitro and in vivo by suppressing the STAT3 pathway [22] and induced HepaRG cell death through S-phase cell cycle arrest and apoptosis [23].…”

The association of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α protein expression with clinicopathological characteristics in papillary thyroid carcinoma: A meta-analysis

“…HIF-1α is mainly involved in the adaptive response in the early and acute phase of hypoxia, while HIF-2α is mainly involved in the long-term and chronic hypoxia of tumors. [ 12 ] Studies have shown that HIF-1α and HIF-2α are highly expressed in a variety of human cancers, such as oral cancer, [ 13 ] gastric cancer, [ 14 ] pancreatic cancer, [ 15 ] non-small cell lung cancer, [ 16 ] breast cancer, [ 17 ] cervical cancer, [ 18 ] prostate cancer, [ 19 ] and glioblastoma, [ 20 ] etc.…”