Cancer Cell
Volume 19, Issue 3, 8 March 2011, Pages 401-415
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Article
Angiopoietin-like 4 Protein Elevates the Prosurvival Intracellular O2:H2O2 Ratio and Confers Anoikis Resistance to Tumors

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Summary

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 O2. A high ratio of O2:H2O2 oxidizes/activates Src, triggering the PI3K/PKBα and ERK prosurvival pathways to confer anoikis resistance, thus promoting tumor growth. ANGPTL4 deficiency results in diminished O2 production and a reduced O2:H2O2 ratio, creating a cellular environment conducive to apoptosis. ANGPTL4 is an important redox player in cancer and a potential therapeutic target.

Highlights

► Elevated expression of ANGPTL4 is a common feature of many human tumor types ► ANGPTL4 binds integrins to stimulate the NADPH oxidase-dependent production of O2 ► ANGPTL4 sustains a high O2:H2O2 ratio to activate prosurvival pathways ► Suppression of ANGPTL4 impairs tumor growth and enhances anoikis/apoptosis

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