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

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 (PKC) by dephosphorylating the kinases...

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Autores principales: Liu, Jianyu, Weiss, Heidi L., Rychahou, Piotr, Jackson, Lindsey N., Evers, B. Mark, Gao, Tianyan
Formato: Texto
Lenguaje:English
Publicado: 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921630/
https://www.ncbi.nlm.nih.gov/pubmed/19079341
http://dx.doi.org/10.1038/onc.2008.450
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author Liu, Jianyu
Weiss, Heidi L.
Rychahou, Piotr
Jackson, Lindsey N.
Evers, B. Mark
Gao, Tianyan
author_facet Liu, Jianyu
Weiss, Heidi L.
Rychahou, Piotr
Jackson, Lindsey N.
Evers, B. Mark
Gao, Tianyan
author_sort Liu, Jianyu
collection PubMed
description 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 (PKC) 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 (IHC) 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 (PI3K) 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, re-expression 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.
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spelling pubmed-29216302010-08-16 Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis Liu, Jianyu Weiss, Heidi L. Rychahou, Piotr Jackson, Lindsey N. Evers, B. Mark Gao, Tianyan Oncogene Article 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 (PKC) 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 (IHC) 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 (PI3K) 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, re-expression 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. 2008-12-15 2009-02-19 /pmc/articles/PMC2921630/ /pubmed/19079341 http://dx.doi.org/10.1038/onc.2008.450 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Liu, Jianyu
Weiss, Heidi L.
Rychahou, Piotr
Jackson, Lindsey N.
Evers, B. Mark
Gao, Tianyan
Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis
title Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis
title_full Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis
title_fullStr Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis
title_full_unstemmed Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis
title_short Loss of PHLPP expression in colon cancer: Role in proliferation and tumorigenesis
title_sort loss of phlpp expression in colon cancer: role in proliferation and tumorigenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921630/
https://www.ncbi.nlm.nih.gov/pubmed/19079341
http://dx.doi.org/10.1038/onc.2008.450
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