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Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.

ABSTRACT: PHLPP (PH domain leucine-rich repeats protein phosphatase) represents a family of novel Ser/Thr protein phosphatases. Two highly related isoforms in this family, PHLPP1 and PHLPP2, have been identified to serve as negative regulators of Akt and protein kinase C by dephosphorylating the kinases directly. In this study, we examined the expression pattern of both PHLPP isoforms in colorectal cancer specimens and the adjacent normal mucosa using immunohistochemical staining. We found that the expression of PHLPP1 or PHLPP2 isoform was lost or decreased in 78 and 86% of tumor tissues, respectively. Stable overexpression of either PHLPP isoform in colon cancer cells decreased the rate of cell proliferation and sensitized the cells to growth inhibition induced by the phosphoinositide-3 kinase inhibitor, LY294002, whereas knockdown of either PHLPP isoform by shRNA promoted the proliferation of DLD1 cells. In addition, we demonstrated that the PHLPP-mediated growth inhibition in colon cancer cells was largely rescued by overexpression of a constitutively active Akt. Moreover, reexpression of either PHLPP isoform in HCT116 cells inhibited tumor growth in vivo. Taken together, our results strongly support a tumor suppressor role of PHLPP in colon cancer.

SUBMITTER: Liu J

PROVIDER: S-EPMC2921630 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.

Liu J J Weiss H L HL Rychahou P P Jackson L N LN Evers B M BM Gao T T

Oncogene 20081215 7

PHLPP (PH domain leucine-rich repeats protein phosphatase) represents a family of novel Ser/Thr protein phosphatases. Two highly related isoforms in this family, PHLPP1 and PHLPP2, have been identified to serve as negative regulators of Akt and protein kinase C by dephosphorylating the kinases directly. In this study, we examined the expression pattern of both PHLPP isoforms in colorectal cancer specimens and the adjacent normal mucosa using immunohistochemical staining. We found that the expres ...[more]

PMID: 19079341

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Project description:Background & aims: Indoleamine 2,3 dioxygenase-1 (IDO1) catabolizes tryptophan along the kynurenine pathway. Although IDO1 is expressed in inflamed and neoplastic epithelial cells of the colon, its role in colon tumorigenesis is not well understood. We used genetic and pharmacologic approaches to manipulate IDO1 activity in mice with colitis-associated cancer and human colon cancer cell lines.Methods: C57Bl6 wild-type (control), IDO1-/-, Rag1-/-, and Rag1/IDO1 double-knockout mice were exposed to azoxymethane and dextran sodium sulfate to induce colitis and tumorigenesis. Colitis severity was assessed by measurements of disease activity, cytokine levels, and histologic analysis. In vitro experiments were conducted using HCT 116 and HT-29 human colon cancer cells. 1-methyl tryptophan and small interfering RNA were used to inhibit IDO1. Kynurenine pathway metabolites were used to simulate IDO1 activity.Results: C57Bl6 mice given pharmacologic inhibitors of IDO1 and IDO1-/- mice had lower tumor burdens and reduced proliferation in the neoplastic epithelium after administration of dextran sodium sulfate and azoxymethane than control mice. These reductions also were observed in Rag1/IDO1 double-knockout mice compared with Rag1-/- mice (which lack mature adaptive immunity). In human colon cancer cells, blockade of IDO1 activity reduced nuclear and activated ?-catenin, transcription of its target genes (cyclin D1 and Axin2), and, ultimately, proliferation. Exogenous administration of IDO1 pathway metabolites kynurenine and quinolinic acid led to activation of ?-catenin and proliferation of human colon cancer cells, and increased tumor growth in mice.Conclusions: IDO1, which catabolizes tryptophan, promotes colitis-associated tumorigenesis in mice, independent of its ability to limit T-cell-mediated immune surveillance. The epithelial cell-autonomous survival advantage provided by IDO1 to colon epithelial cells indicate its potential as a therapeutic target.

Project description:There is growing evidence that individuals with colonic adenomas and carcinomas harbor a distinct microbiota. Alterations to the gut microbiota may allow the outgrowth of bacterial populations that induce genomic mutations or exacerbate tumor-promoting inflammation. In addition, it is likely that the loss of key bacterial populations may result in the loss of protective functions that are normally provided by the microbiota. We explored the role of the gut microbiota in colon tumorigenesis by using an inflammation-based murine model. We observed that perturbing the microbiota with different combinations of antibiotics reduced the number of tumors at the end of the model. Using the random forest machine learning algorithm, we successfully modeled the number of tumors that developed over the course of the model on the basis of the initial composition of the microbiota. The timing of antibiotic treatment was an important determinant of tumor outcome, as colon tumorigenesis was arrested by the use of antibiotics during the early inflammation period of the murine model. Together, these results indicate that it is possible to predict colon tumorigenesis on the basis of the composition of the microbiota and that altering the gut microbiota can alter the course of tumorigenesis. IMPORTANCE Mounting evidence indicates that alterations to the gut microbiota, the complex community of bacteria that inhabits the gastrointestinal tract, are strongly associated with the development of colorectal cancer. We used antibiotic perturbations to a murine model of inflammation-driven colon cancer to generate eight starting communities that resulted in various severities of tumorigenesis. Furthermore, we were able to quantitatively predict the final number of tumors on the basis of the initial composition of the gut microbiota. These results further bolster the evidence that the gut microbiota is involved in mediating the development of colorectal cancer. As a final proof of principle, we showed that perturbing the gut microbiota in the midst of tumorigenesis could halt the formation of additional tumors. Together, alteration of the gut microbiota may be a useful therapeutic approach to preventing and altering the trajectory of colorectal cancer.

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Dataset Information

Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.

Publications

Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis.

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