β-Pentagalloyl-Glucose Sabotages Pancreatic Cancer Cells and Ameliorates Cachexia in Tumor-Bearing Mice

Abstract

Pancreatic cancer cells overexpress the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R). Activating these receptors, insulin and insulin-like growth factor-1 increase the growth and glycolysis of pancreatic cancer cells. The high glycolysis in pancreatic cancer cells increases whole-body energy expenditure and is therefore involved in the pathogenesis of cancer cachexia. The antagonism of IR and IGF1R may sabotage pancreatic cancer cells and attenuate cancer cachexia. Previous studies have shown that the intracellular regulating system of IR/IGF1R may be functionally interrelated to another intracellular system whose master regulator is hypoxia-inducible factor-1 (HIF-1). In this study, we investigated how the IR/IGF1R and HIF-1 systems are interrelated in pancreatic cancer cells. We also investigated whether a phytochemical, penta-O-galloyl-[Formula: see text]-D-glucose ([Formula: see text]-PGG), antagonizes IR/IGF1R, sabotages pancreatic cancer cells and alleviates cancer cachexia. We found in MiaPaCa2 pancreatic cancer cells that IR/IGF1R activation increased both the [Formula: see text]-subunit of HIF-1 and caveolin-1. This result suggests that IR/IGF1R, HIF-1[Formula: see text], and caveolin-1 may constitute a feed-forward loop to mediate the effect of IR/IGF1R activation. [Formula: see text]-PGG inhibited IR/IGF1R activity and decreased glycolytic enzymes in MiaPaCa2 and Panc-1 pancreatic cancer cells. When MiaPaCa2 cells were transplanted in athymic mice, their growth was inhibited by [Formula: see text]-PGG or by a HIF-1[Formula: see text] inhibitor, rhein. [Formula: see text]-PGG and rhein also decreased glycolytic enzymes in the tumor grafts and reduced liver gluconeogenesis, skeletal-muscle proteolysis and fat lipolysis in the tumor carriers. Cancer-induced body-weight loss, however, was prevented by [Formula: see text]-PGG but not rhein. In conclusion, [Formula: see text]-PGG combats pancreatic cancer cells and cures cancer cachexia.