Emodin and rhein decrease levels of hypoxia-inducible factor-1α in human pancreatic cancer cells and attenuate cancer cachexia in athymic mice carrying these cells

Abstract

The transcription factor hypoxia-inducible factor-1 (HIF-1) consists of oxygen-sensitive HIF-1α and constitutive HIF-1β. HIF-1α is undetectable in normal cells, but cancer cells frequently express HIF-1α to support their growth, angiogenesis, and high glycolysis (also known as the Warburg effect). The Warburg effect in cancer cells increases energy expenditure and thus participates in cancer-induced metabolic disorder, cancer cachexia. In the present study, we investigated whether two components of Rheum palmatum, emodin and rhein, inhibited HIF-1α expression in human pancreatic cancer cells and whether the inhibiting effect, if any, attenuated cancer cachexia. Using Western blotting, we demonstrated that emodin and rhein decreased HIF-1α expression in MiaPaCa2 and four other human pancreatic cancer cell lines. We also examined HIF-1α expression when MiaPaCa2 cells were exposed to PX-478, noscapine, and phenethyl isothiocyanate, as these compounds were known to inhibit HIF-1α expression in different cancer cells. PX-478 and noscapine inhibited HIF-1α expression to a less extent than emodin and rhein, and phenethyl isothiocyanate did not inhibit HIF-1α expression in tested concentrations. We obtained evidence that emodin and rhein decreased HIF-1α by decreasing its biosynthesis but not gene transcription or protein stability. When MiaPaCa2 cells were implanted in athymic mice, emodin and rhein inhibited cancer-cell growth and HIF-1α expression. In these athymic mice, emodin and rhein also attenuated two pathological constituents of cancer cachexia, namely high hepatic gluconeogenesis and skeletal-muscle proteolysis. In conclusion, emodin and rhein decrease pancreatic cancer cell's growth and HIF-1α expression and attenuate cancer cachexia in the athymic mice carrying the cancer cells.