Angiopoietin-like 4 Protein Elevates the Prosurvival Intracellular O-2(-):H2O2 Ratio and Confers Anoikis Resistance to Tumors

P.C. Zhu, M.J. Tan, R.L. Huang, C.K. Tan, H.C. Chong, M. Pal, C.R.I. Lam, P. Boukamp, J.Y. Pan, S.H. Tan, A.H. Kersten, H.Y. Li, J.L. Ding, N.S. Tan

Research output: Contribution to journalArticleAcademicpeer-review

169 Citations (Scopus)

Abstract

Cancer is a leading cause of death worldwide. Tumor cells exploit various signaling pathways to promote their growth and metastasis. To our knowledge, the role of angiopoietin-like 4 protein (ANGPTL4) in cancer remains undefined. Here, we found that elevated ANGPTL4 expression is widespread in tumors, and its suppression impairs tumor growth associated with enhanced apoptosis. Tumor-derived ANGPTL4 interacts with integrins to stimulate NADPH oxidase-dependent production of O-2(-). A high ratio of O-2(-):H2O2 oxidizes/activates Src, triggering the PI3K/PKB alpha and ERK prosurvival pathways to confer anoikis resistance, thus promoting tumor growth. ANGPTL4 deficiency results in diminished O-2(-) production and a reduced O-2(-):H2O2 ratio, creating a cellular environment conducive to apoptosis. ANGPTL4 is an important redox player in cancer and a potential therapeutic target.
Original languageEnglish
Pages (from-to)401-415
JournalCancer Cell
Volume19
Issue number3
DOIs
Publication statusPublished - 2011

Keywords

  • prostate-cancer cells
  • beta-carotene
  • cardiovascular-disease
  • hydrogen-peroxide
  • redox regulation
  • nadph oxidase
  • superoxide
  • metastasis
  • survival
  • expression

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