Background & Aims: PHLPP, a novel family of protein phosphatases, plays an important role in balancing cellular signaling pathways that control cell death and proliferation. Loss of PHLPP expression promotes colorectal cancer (CRC) tumorigenesis and progression. Intestine epithelial cells (IECs) apoptosis contributes to the development of inflammatory bowel disease (IBD), and patients with IBD are at increased risk for CRC. We investigated the functional importance of PHLPP in intestinal inflammation.
Methods: Both Phlpp1 and Phlpp2 genes were deleted in mice. The effect of PHLPP double knockout (DKO) on the development of acute colitis was examined in dextran sulfate sodium salt (DSS)-treated mice. Biochemical and histological analyses were conducted to determine the extent of tissue inflammation and colon epithelial cell apoptosis. The expression of PHLPP proteins was examined in DSS-treated mice and IBD patient samples.
Results: In ulcerative colitis and Crohn's disease patient samples, both PHLPP1 and PHLPP2 protein expression was markedly decreased in colitis tissues compared to that in uninvolved tissues. In mice, PHLPP expression was significantly reduced in colonic epithelial cells following induction of colitis by DSS. Mechanistically, the inflammation-induced downregulation of PHLPP was mediated through proteasome-dependent protein degradation. Compared with wild-type mice, PHLPP DKO mice were protected from colitis induced by the DSS treatment as demonstrated by lower histopathological scores, and this reduced susceptibility to colitis was associated with decreased apoptosis and increased Akt activity in colonic epithelial cells. Furthermore, epithelial organoids derived from colon and small intestine of PHLPP DKO mice are more resistant to inflammation-induced apoptosis upon Akt activation.
Conclusion: These results indicated that PHLPP contributes to the pathogenesis of colitis by controlling epithelial cell apoptosis. Downregulation of PHLPP at the onset of inflammation plays a role in protecting intestinal epithelial cell injury by inhibiting apoptosis. However, prolonged PHLPP-loss may promote colon cancer initiation in IBD patients.
Citation Format: Yang-an Wen, Xin Li, Tatiana Goretsky, Terrence A. Barrett, Tianyan Gao. Loss of PHLPPs protects against colitis by inhibiting epithelial apoptosis through upregulating AKT activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1030. doi:10.1158/1538-7445.AM2015-1030