Abstract
c‐Src is a commonly upregulated oncogene in colorectal cancer. High fat diet (HFD) augments the numbers and function of Lgr5+ intestinal stem cells (ISCs), increasing the capacity of these stems cells to initiate tumors. Discoveries in triple negative breast cancer models and patient specimens suggest that mitochondrial reprogramming to fatty acid oxidation (FAO) activates c‐Src. Here, we determined the role of FAO induced by HFD on c‐Src activation and ISC self‐renewal. Lgr5‐EGFP‐IRES‐creERT2 (Lrg5‐EGFP) knock‐in mice were fed a dietary chow consisting of 45% kcal fat or a low fat matching diet ad libitum from 8 to 20 weeks of age. Beginning at age 10 weeks, mice were i.p. injected with 20 mg/kg Etomoxir (ETX), an inhibitor of FAO, twice per week. Intestinal enteroids derived from Lgr5‐EGFP mice were treated with constituents of HFD (30 μM palmitic acid and 30 μM oleic acid) every 3 days for 2 weeks ± 20 μM PP2, a Src inhibitor. Numbers of intestinal Lgr5‐GFP+ cells were quantitated and isolated by flow cytometry and expression of c‐Src target gene Cyclin D1 and ISC self‐renewal gene Olfm4 were measured by qPCR. c‐Src activation was measured in human colon cancer cell lines HCT‐116 and Caco2 treated with 200 μM ETX or 10 mM L‐carnitine (FAO activator) for 16 hr. HFD increased the number of Lgr5+ ISCs and expression of Cyclin D1 and Olfm4, which were prevented by ETX. PP2 inhibition of c‐Src in enteroids prevented the palmitic acid/oleic acid‐induced increase in Lgr5+ ISC numbers. ETX decreased and L‐carnitine induced c‐Src activity in HCT‐116 and Caco2 cells. Our data provide novel evidence that the Src pathway plays an important role in ISC response to constituents of HFD.Support or Funding InformationCollaborative Faculty Research Investment Program (CFRIP), Baylor Scott & White Health and Baylor College of MedicineThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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