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Deficiency of Phospholipase A2 Group 7 Decreases Intestinal Polyposis and Colon Tumorigenesis in ApcMin/+ Mice

Platelet-activating factor (PAF) is a naturally occurring phospholipid that mediates diverse effects such as physiological and pathological inflammation, immunosuppression, and cancer. Several lines of evidence support both positive and negative roles for PAF in carcinogenesis. PAF stimulates cell g... Full description

Journal Title: Cancer Research 05/01/2013, Vol.73(9), pp.2806-2816
Main Author: Xu, C.
Other Authors: Reichert, E. C. , Nakano, T. , Lohse, M. , Gardner, A. A. , Revelo, M. P. , Topham, M. K. , Stafforini, D. M.
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0008-5472 ; E-ISSN: 1538-7445 ; DOI: http://dx.doi.org/10.1158/0008-5472.CAN-12-2374
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recordid: crossref10.1158/0008-5472.CAN-12-2374
title: Deficiency of Phospholipase A2 Group 7 Decreases Intestinal Polyposis and Colon Tumorigenesis in ApcMin/+ Mice
format: Article
creator:
  • Xu, C.
  • Reichert, E. C.
  • Nakano, T.
  • Lohse, M.
  • Gardner, A. A.
  • Revelo, M. P.
  • Topham, M. K.
  • Stafforini, D. M.
subjects:
  • Medicine
ispartof: Cancer Research, 05/01/2013, Vol.73(9), pp.2806-2816
description: Platelet-activating factor (PAF) is a naturally occurring phospholipid that mediates diverse effects such as physiological and pathological inflammation, immunosuppression, and cancer. Several lines of evidence support both positive and negative roles for PAF in carcinogenesis. PAF stimulates cell growth, oncogenic transformation, and metastasis, but can also limit proliferation and induce apoptosis. The biological context and microenvironment seem to define whether PAF has pro- or anticarcinogenic effects. To investigate the role of exacerbated PAF signaling in colon cancer, we conducted cell-based and in vivo studies using genetically engineered mice lacking expression of phospholipase A2 group 7 (PLA2G7), an enzyme that specifically metabolizes PAF and structurally related glycerophospholipids. Absence of Pla2g7 robustly decreased intestinal polyposis and colon tumor formation in Apc(Min)(/+) mice, suggesting an antitumorigenic role for PAF in settings characterized by aberrant function of the tumor suppressor Adenomatous polyposis coli (Apc). In colonic epithelial cells, exposure to a PAF analog led to dephosphorylation of Akt at serine-473 and induction of apoptosis. The mechanism of this response involved formation of a complex between β-arrestin 1 and the Akt phosphatase PHLPP2, and activation of the intrinsic pathway of apoptosis. Our results suggest that strategies based on inhibiting PLA2G7 activity or increasing PAF-mediated signaling hold promise for the treatment of intestinal malignancies that harbor mutations in APC.
language: eng
source:
identifier: ISSN: 0008-5472 ; E-ISSN: 1538-7445 ; DOI: http://dx.doi.org/10.1158/0008-5472.CAN-12-2374
fulltext: fulltext
issn:
  • 00085472
  • 0008-5472
  • 15387445
  • 1538-7445
url: Link


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titleDeficiency of Phospholipase A2 Group 7 Decreases Intestinal Polyposis and Colon Tumorigenesis in ApcMin/+ Mice
creatorXu, C. ; Reichert, E. C. ; Nakano, T. ; Lohse, M. ; Gardner, A. A. ; Revelo, M. P. ; Topham, M. K. ; Stafforini, D. M.
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descriptionPlatelet-activating factor (PAF) is a naturally occurring phospholipid that mediates diverse effects such as physiological and pathological inflammation, immunosuppression, and cancer. Several lines of evidence support both positive and negative roles for PAF in carcinogenesis. PAF stimulates cell growth, oncogenic transformation, and metastasis, but can also limit proliferation and induce apoptosis. The biological context and microenvironment seem to define whether PAF has pro- or anticarcinogenic effects. To investigate the role of exacerbated PAF signaling in colon cancer, we conducted cell-based and in vivo studies using genetically engineered mice lacking expression of phospholipase A2 group 7 (PLA2G7), an enzyme that specifically metabolizes PAF and structurally related glycerophospholipids. Absence of Pla2g7 robustly decreased intestinal polyposis and colon tumor formation in Apc(Min)(/+) mice, suggesting an antitumorigenic role for PAF in settings characterized by aberrant function of the tumor suppressor Adenomatous polyposis coli (Apc). In colonic epithelial cells, exposure to a PAF analog led to dephosphorylation of Akt at serine-473 and induction of apoptosis. The mechanism of this response involved formation of a complex between β-arrestin 1 and the Akt phosphatase PHLPP2, and activation of the intrinsic pathway of apoptosis. Our results suggest that strategies based on inhibiting PLA2G7 activity or increasing PAF-mediated signaling hold promise for the treatment of intestinal malignancies that harbor mutations in APC.
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