Angiopoietin-like 4 Protein Elevates the Prosurvival Intracellular O2−:H2O2 Ratio and Confers Anoikis Resistance to Tumors

SummaryCancer 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.

► 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