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Cannabinoids induce pancreatic ?-cell death by directly inhibiting insulin receptor activation.

ABSTRACT: Cannabinoid 1 (CB1) receptors have been previously detected in pancreatic ? cells, where they attenuate insulin action. We now report that CB1 receptors form a heteromeric complex with insulin receptors and the heterotrimeric guanosine triphosphate-binding protein ? subunit G?(i). G?(i) inhibited the kinase activity of the insulin receptor in ? cells by directly binding to the activation loop in the tyrosine kinase domain of the receptor. Consequently, phosphorylation of proapoptotic protein Bad was reduced and its apoptotic activity was stimulated, leading to ?-cell death. Pharmacological blockade or genetic deficiency of CB1 receptors enhanced insulin receptor signaling after injury, leading to reduced blood glucose concentrations and activation of Bad, which increased ?-cell survival. These findings provide direct evidence of physical and functional interactions between CB1 and insulin receptors and suggest a mechanism whereby peripherally acting CB1 receptor antagonists improve insulin action in insulin-sensitive tissues independent of the other metabolic effects of CB1 receptors.

SUBMITTER: Kim W

PROVIDER: S-EPMC3524575 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Cannabinoids induce pancreatic β-cell death by directly inhibiting insulin receptor activation.

Kim Wook W Lao Qizong Q Shin Yu-Kyong YK Carlson Olga D OD Lee Eun Kyung EK Gorospe Myriam M Kulkarni Rohit N RN Egan Josephine M JM

Science signaling 20120320 216

Cannabinoid 1 (CB1) receptors have been previously detected in pancreatic β cells, where they attenuate insulin action. We now report that CB1 receptors form a heteromeric complex with insulin receptors and the heterotrimeric guanosine triphosphate-binding protein α subunit Gα(i). Gα(i) inhibited the kinase activity of the insulin receptor in β cells by directly binding to the activation loop in the tyrosine kinase domain of the receptor. Consequently, phosphorylation of proapoptotic protein Bad ...[more]

PMID: 22434934

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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.

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Cannabinoids induce pancreatic ?-cell death by directly inhibiting insulin receptor activation.

Publications

Cannabinoids induce pancreatic β-cell death by directly inhibiting insulin receptor activation.

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