Abstract 1434: Metformin-induced metabolic changes are k-ras-dependent in animal models of pancreatic cancer
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy, that is very difficult to treat. To date, systemic treatment for PDA, either a single agent or combinations of agents, has shown only modest benefits. Numerous epidemiological studies have reported that metformin (MET), a widely used anti-diabetic drug, provides protective benefits in reducing PDA risk among the diabetic population. Using a stable isotope glucose (GLUC) tracer for dynamic metabolic profiling (SiDMAP), we recently reported that high cholesterol (CHOL) alters the cellular metabolism of MiaPaCa2 (a PDA cell line harboring mutant K-Ras) cells by redirecting glucose-derived acetyl-CoA toward fatty acid (FA) synthesis. This response to MET is depended on the level of intracellular CHOL synthesis. We now performed a SiDMAP study in the LSL-K-RasG12D/+, LSL-Trp53R172H/+, Pdx-1-Cre (KPC) and the LSL-K-RasG12D/+, Pdx-1-Cre (KC) mouse models for PDA, and their wild-type littermates (C57Bl6.129). The mice were treated (or not) with MET (250 mg/kg, i.p. Q5D) and subjected to an Intra Peritoneal GLUC Tolerance Test (IPGTT) pre- and post-MET treatment. The KPC mice with the average tumor volume of 80.83+8.57 mm3 and the KC mice with PanIN lesions (aver. 9 mo old) were put on study. K-Ras mutation, with the presence of the tumor (KPC mice), induced an increase in plasma GLUC production via de novo synthesis by the liver using futile cycling of GLUC derived lactate and pyruvate. MET treatment…
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