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Rgs8‐16 are Required for Energy Homeostasis in Pancreatic Cancer‐Associated Malnutrition
Author(s) -
Zolghadri Yalda,
Ocal Ozhan,
Wilkie Thomas
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.618.10
Subject(s) - kras , pancreas , pancreatic cancer , cancer research , pancreatic intraepithelial neoplasia , knockout mouse , medicine , biology , endocrinology , cancer , carcinogenesis , receptor , colorectal cancer
Pancreatic insufficiency develops by about 5 weeks of age in KC (LSL‐Kras G12D ;p48 Cre ) mice that express Kras G12D in all pancreas cells. Kras mutations (e.g. Kras G12D ) are found in over 90% of human PDA and are an early event in a multistep process leading to PDA. Kras G12D causes dedifferentiation of acinar cells and a drastic reduction in digestive enzymes secreted by the pancreas. KC mice become malnourished but can survive over one year before succumbing to Pancreatic Ductal Adenocarcinoma (PDA). Protein kinase and G‐Protein Coupled Receptor (GPCR) signaling can initiate Ras activation. Regulators of G‐protein Signaling (RGS) proteins are GTPase Activating Proteins (GAPs) that regulate the intensity and duration of Gi‐ and Gq‐coupled GPCR signaling. Activating mutations in Gq have been associated with PDA. We find Rgs8 and Rgs16 expression is induced in Pancreatic Intraepithelial Neoplasia (PanIN) and Intraductal Papillary Mucinous Neoplasm (IPMN) in KC mice by 2 weeks of age. We crossed the Rgs8‐16 double knockout into KC (termed KC‐R) mice to test if Rgs8‐16 are tumor suppressor genes. Most KC‐R mice die before 4 months of age because they can not maintain energy homeostasis to counteract pancreatic insufficiency – Rgs8‐16 are required in liver to conserve energy utilization during malnutrition. Consistent with this finding, the effects of caloric restriction are more severe in Rgs8‐16 dko compared to wild type mice. The effects of Rgs8‐16 deficiency on exocrine pancreas function, acinar‐to‐ductal metaplasia, apoptosis and tumor progression in KC‐R mice are under investigation. Supported by NCI CA161624.