Caspase-3-dependent activation of calcium-independent phospholipase A 2 enhances cell migration in non-apoptotic ovarian cancer cells

Xiaoxian Zhao, Dongmei Wang, Zhenwen Zhao, Yingyi Xiao, Saubhik Sengupta, Yijin Xiao, Renliang Zhang, Kirsten Lauber, Sebastian Wesselborg, Li Feng, Tyler M. Rose, Yue Shen, Junjie Zhang, Glenn Prestwich, Yan Xu

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

Calcium-independent phospholipase A2 (iPLA2) plays a pivotal role in phospholipid remodeling and many other biological processes, including inflammation and cancer development. iPLA2 can be activated by caspase-3 via a proteolytic process in apoptotic cells. In this study we identify novel signaling and functional loops of iPLA2 activation leading to migration of non-apoptotic human ovarian cancer cells. The extracellular matrix protein, laminin-10/11, but not collagen I, induces integrin- and caspase-3-dependent cleavage and activation of overexpressed and endogenous iPLA2. The truncated iPLA2 (amino acids 514-806) generates lysophosphatidic acid and arachidonic acid. Arachidonic acid is important for enhancing cell migration toward laminin-10/11. Lysophosphatidic acid activates Akt that in turn acts in a feedback loop to block the cleavage of poly-(ADP-ribose) polymerase and DNA fragmentation factor as well as prevent apoptosis. By using pharmacological inhibitors, blocking antibodies, and genetic approaches (such as point mutations, dominant negative forms of genes, and siRNAs against specific targets), we show that β1, but not β4, integrin is involved in iPLA2 activation and cell migration to laminin-10/11. The role of caspase-3 in iPLA2 activation and cell migration are supported by several lines of evidence. 1) Point mutation of Asp513 (a cleavage site of caspase-3 in iPLA 2) to Ala blocks laminin-10/11-induced cleavage and activation of overexpressed iPLA2, whereas mutation of Asp733 to Ala has no such effect, 2) treatment of inhibitors or a small interfering RNA against caspase-3 results in decreased cell migration toward laminin-10/11, and 3) selective caspase-3 inhibitor blocks cleavage of endogenous iPLA2 induced by laminin-10/11. Importantly, small interfering RNA-mediated down-regulation of endogenous iPLA2 expression in ovarian carcinoma HEY cells results in decreased migration toward laminin, suggesting that our findings are pathophysiologically important.

Original languageEnglish (US)
Pages (from-to)29357-29368
Number of pages12
JournalJournal of Biological Chemistry
Volume281
Issue number39
DOIs
StatePublished - Sep 29 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zhao, X., Wang, D., Zhao, Z., Xiao, Y., Sengupta, S., Xiao, Y., Zhang, R., Lauber, K., Wesselborg, S., Feng, L., Rose, T. M., Shen, Y., Zhang, J., Prestwich, G., & Xu, Y. (2006). Caspase-3-dependent activation of calcium-independent phospholipase A 2 enhances cell migration in non-apoptotic ovarian cancer cells. Journal of Biological Chemistry, 281(39), 29357-29368. https://doi.org/10.1074/jbc.M513105200