Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis

J. Liu, H. L. Weiss, P. Rychahou, L. N. Jackson, B. M. Evers, T. Gao

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

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.

Original languageEnglish
Pages (from-to)994-1004
Number of pages11
JournalOncogene
Volume28
Issue number7
DOIs
StatePublished - Feb 19 2009

Bibliographical note

Funding Information:
We thank UTMB flow cytometry core for assistance with the flow cytometry analysis, and Dr Alexandra Newton at University of California San Diego for providing the wild-type and mutant Akt and PKC bII expression constructs. This work was supported by NIH K01 CA10209-05 (TG), American Cancer Society RSG0822001TBE (TG) and R01CA104748 (BME).

Keywords

  • Akt
  • Colon cancer cells
  • PHLPP
  • Protein kinase C
  • Tumorigenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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