HT-29 human colon cancer cell proliferation is regulated by cytosolic phospholipase A2α dependent PGE2 via both PKA and PKB pathways

Liz Kisslov, Nurit Hadad, Marina Rosengraten, Rachel Levy

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Cytosolic phospholipase A2α (cPLA2α) up-regulation has been reported in human colorectal cancer cells, thus we aimed to elucidate its role in the proliferation of the human colorectal cancer cell line, HT-29. EGF caused a rapid activation of cPLA2α which coincided with a significant increase in cell proliferation. The inhibition of cPLA2α activity by pyrrophenone or by antisense oligonucleotide against cPLA2α (AS) or inhibition of prostaglandin E 2 (PGE2) production by indomethacin resulted with inhibition of cell proliferation, that was restored by addition of PGE 2. The secreted PGE2 activated both protein kinase A (PKA) and PKB/Akt pathways via the EP2 and EP4 receptors. Either, the PKA inhibitor (H-89) or the PKB/Akt inhibitor (Ly294002) caused a partial inhibition of cell proliferation which was restored by PGE2. But, inhibited proliferation in the presence of both inhibitors could not be restored by addition of PGE2. AS or H-89, but not Ly294002, inhibited CREB activation, suggesting that CREB activation is mediated by PKA. AS or Ly294002, but not H-89, decreased PKB/Akt activation as well as the nuclear localization of β-catenin and cyclin D1 and increased the plasma membrane localization of β-catenin with E-cadherin, suggesting that these processes are regulated by the PKB pathway. Similarly, Caco-2 cells exhibited cPLA2α dependent proliferation via activation of both PKA and PKB/Akt pathways. In conclusion, our findings suggest that the regulation of HT-29 proliferation is mediated by cPLA2α-dependent PGE2 production. PGE2 via EP induces CREB phosphorylation by the PKA pathway and regulates β-catenin and cyclin D1 cellular localization by PKB/Akt pathway.

Original languageEnglish
Pages (from-to)1224-1234
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1821
Issue number9
DOIs
StatePublished - 1 Sep 2012
Externally publishedYes

Keywords

  • CREB
  • Cytosolic phospolipase Aα
  • PGE
  • PKA
  • PKB/Akt
  • β-Catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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