Abstract
Activation of pancreatic stellate cells (PSCs) initiates pancreatic fibrosis in chronic pancreatitis and furnishes a niche that enhances the malignancy of pancreatic cancer cells (PCCs) in pancreatic ductal adenocarcinoma (PDAC). Resveratrol (RSV), a natural polyphenol, exhibits potent antioxidant and anticancer effects. However, whether and how RSV influences the biological properties of activated PSCs and the effects of these changes on tumor remain unknown. In the present study, we found that RSV impeded hydrogen peroxide-driven reactive oxygen species- (ROS-) induced activation, invasion, migration, and glycolysis of PSCs. In addition, miR-21 expression in activated PSCs was downregulated after RSV treatment, whereas the PTEN protein level increased. miR-21 silencing attenuated ROS-induced activation, invasion, migration, and glycolysis of PSCs, whereas the overexpression of miR-21 rescued the responses of PSCs treated with RSV. Moreover, RSV or N-acetyl-L-cysteine (NAC) administration or miR-21 knockdown in PSCs reduced the invasion and migration of PCCs in coculture, and the effects of RSV were partly reversed by miR-21 upregulation. Collectively, RSV inhibits PCC invasion and migration through suppression of ROS/miR-21-mediated activation and glycolysis in PSCs. Therefore, targeting miR-21-mediated glycolysis by RSV in tumor stroma may serve as a new strategy for clinical PDAC prevention or treatment.
Highlights
With a 7% five-year survival rate and more than 43,000 estimated deaths per year in the United States, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and causes serious public health issues and cancer burden [1]
We demonstrated that RSV may inhibit reactive oxygen species- (ROS-)promoted activation, invasion, and glycolysis of pancreatic stellate cells (PSCs) via suppression of miR-21
The human pancreatic cancer cell line Panc-1 was purchased from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China) and cultured in Dulbecco’s modified Eagle medium (DMEM) containing 10% FBS (HyClone, Logan, UT, USA), 100 μg/mL ampicillin, and 100 μg/mL streptomycin at 37°C with 5% CO2 and 95% air
Summary
With a 7% five-year survival rate and more than 43,000 estimated deaths per year in the United States, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and causes serious public health issues and cancer burden [1]. Aggressive growth and metastasis, lack of early diagnosis, low rates of curative resection, and poor responses to radiation and chemotherapy characterize the dismal prognosis and treatment of PDAC. Current therapies focus on epithelial cancer cells, which contribute to the rapid proliferation and malignancy of the tumor. PSC activation, which is characterized by a decrease in vitamin A-containing lipid droplets and increased expression of α-SMA and collagen-I, is pivotal in the development of pancreatic fibrosis and the malignant behavior of PDAC [6, 7]. The interaction between PSCs (cancer-associated fibroblasts) and tumor cells is mediated by diverse secreted soluble factors such as extracellular matrix proteins, cytokines, and integrins [10], and disrupting this connection may provide novel approaches to cancer therapy
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