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?-Mangostin inhibits hypoxia-driven ROS-induced PSC activation and pancreatic cancer cell invasion.

ABSTRACT: Recent advances indicating a key role of microenvironment for tumor progression, we investigated the role of PSCs and hypoxia in pancreatic cancer aggressiveness, and examined the potential protective effect of ?-mangostin on hypoxia-driven pancreatic cancer progression. Our data indicate that hypoxic PSCs exploit their oxidative stress due to hypoxia to secrete soluble factors favouring pancreatic cancer invasion. ?-Mangostin suppresses hypoxia-induced PSC activation and pancreatic cancer cell invasion through the inhibition of HIF-1? stabilization and GLI1 expression. Increased generation of hypoxic ROS is responsible for HIF-1? stabilization and GLI1 upregulation. Therefore, ?-mangostin may be beneficial in preventing hypoxia-induced pancreatic cancer progression.

SUBMITTER: Lei J

PROVIDER: S-EPMC4005872 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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α-Mangostin inhibits hypoxia-driven ROS-induced PSC activation and pancreatic cancer cell invasion.

Lei Jianjun J Huo Xiongwei X Duan Wanxing W Xu Qinhong Q Li Rong R Ma Jiguang J Li Xuqi X Han Liang L Li Wei W Sun Hao H Wu Erxi E Ma Qingyong Q

Cancer letters 20140207 1

Recent advances indicating a key role of microenvironment for tumor progression, we investigated the role of PSCs and hypoxia in pancreatic cancer aggressiveness, and examined the potential protective effect of α-mangostin on hypoxia-driven pancreatic cancer progression. Our data indicate that hypoxic PSCs exploit their oxidative stress due to hypoxia to secrete soluble factors favouring pancreatic cancer invasion. α-Mangostin suppresses hypoxia-induced PSC activation and pancreatic cancer cell ...[more]

PMID: 24513179

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Project description:Pancreatic cancer is characterized by a hypoxic tumor microenvironment, which is primarily caused by massive fibrosis with pancreatic stellate cells (PSCs) as a main component. Our previous studies have shown that resveratrol can significantly inhibit pancreatic cancer. However, whether resveratrol can inhibit hypoxia-induced cancer development remains unclear. The objective of this study was to explore whether PSCs and hypoxia synergistically mediate aggressiveness in pancreatic cancer and detect the potential pleiotropic protective effects of resveratrol on hypoxia-induced pancreatic cancer progression. Human PSCs were treated with vehicle or resveratrol under normoxic or hypoxic conditions (3% O2), and PSC activation was assessed by immunofluorescence staining. SiRNA was used to silence hypoxia-inducible factor 1 (HIF-1) expression. The invasive capacity of Panc-1 and Mia Paca-2 cells cocultured with conditioned medium from PSCs was assessed by Transwell assays. To examine tumor formation kinetics, KPC (LSL-KrasG12D/+, Trp53fl/+, and Pdx1-Cre) mice were sacrificed at different time points. To investigate the antitumor effects of resveratrol in vivo, 8-wk-old KPC mice were divided into two groups and treated daily with or without 50 mg/kg resveratrol. Our data indicate that hypoxia induces PSC activation via HIF-1 and that the interleukin 6, vascular endothelial growth factor A, and stromal cell-derived factor 1 derived from activated PSCs promote both invasion and the epithelial-mesenchymal transition and inhibit apoptosis in pancreatic cancer cells. However, resveratrol inhibits hypoxia-induced PSC activation, blocks the interplay between PSCs and pancreatic cancer cells, and suppresses the malignant progression of pancreatic cancer and stromal desmoplasia in a KPC mouse model. Our data highlight that activated PSCs and intratumoral hypoxia are essential targets for novel strategies to prevent tumor-microenvironment interactions. Furthermore, the polyphenolic compound resveratrol effectively ameliorates the malignant progression of pancreatic ductal adenocarcinoma.

Dataset Information

?-Mangostin inhibits hypoxia-driven ROS-induced PSC activation and pancreatic cancer cell invasion.

Publications

α-Mangostin inhibits hypoxia-driven ROS-induced PSC activation and pancreatic cancer cell invasion.

Similar Datasets

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