Resveratrol inhibits hypoxia-driven ROS-induced invasive and migratory ability of pancreatic cancer cells via suppression of the Hedgehog signaling pathway

A hypoxic microenvironment is commonly found in the central region of solid tumors, including pancreatic cancer. Our previous study revealed that resveratrol plays an important role in suppressing the proliferation and EMT of pancreatic cancer cells. However, whether resveratrol could suppress hypoxia-induced cancer progression and the underlying mechanisms have not been fully elucidated. The aim of the present study was to evaluate whether resveratrol affects hypoxia-induced reactive oxygen species (ROS) production and the activation of the Hedgehog (Hh) signaling pathway as well as the invasion of pancreatic cancer. The human pancreatic cancer cell lines, BxPC-3 and Panc-1, were subjected to a hypoxic condition and three different concentrations of resveratrol. The intracellular ROS were determined using 2,7-dichlorodihydrofluorecein diacetate. Wound healing and Transwell invasion assays were used to detect the migratory and invasive potential of the cancer cells. Metastatic-related and Hh signaling-related factors were detected by qRT-PCR and western blot analysis. Immunofluorescence staining was used to test the nuclear translocation of GLI1. The results showed that the hypoxia-induced production of ROS was decreased by resveratrol in a concentration-dependent manner. Resveratrol significantly inhibited the hypoxia-stimulated invasion and migration of pancreatic cancer cells. Resveratrol inhibited hypoxia-induced HIF-1 alpha protein expression. Resveratrol also suppressed hypoxia-induced expression of metastatic-related factors, uPA and MMP2. In addition, resveratrol markedly inhibited hypoxia-mediated activation of the Hh signaling pathway. Furthermore, the antioxidant N-acetylcysteine (NAC) significantly suppressed the invasive and migratory ability of pancreatic cancer cells during hypoxia. Taken together, these data indicate that resveratrol plays an important role in suppressing hypoxia-driven ROS-induced pancreatic cancer progression by inhibiting the Hh signaling pathway, providing evidence that resveratrol may be a potential candidate for the chemoprevention of cancer.