Angiopoietin-like 4 protein elevates the prosurvival intracellular O2(-):H2O2 ratio and confers anoikis resistance to tumors.

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)(-):H(2)O(2) oxidizes/activates Src, triggering the PI3K/PKBα 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)(-):H(2)O(2) ratio, creating a cellular environment conducive to apoptosis. ANGPTL4 is an important redox player in cancer and a potential therapeutic target.

• Authors: Pengcheng Zhu, Ming Jie Tan, Royston-Luke Huang, Chek Kun Tan, Han Chung Chong, Mintu Pal, Chee Ren Ivan Lam, Petra Boukamp, Jiun Yit Pan, Suat Hoon Tan, Sander Kersten, Hoi Yeung Li, Jeak Ling Ding, Nguan Soon Tan
• Journal: Cancer cell (Cancer Cell) Vol. 19 Issue 3 Pg. 401-15 (Mar 08 2011) ISSN: 1878-3686 [Electronic] United States
• PMID: 21397862 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• ANGPTL4 protein, human
• Angiopoietin-Like Protein 4
• Angiopoietins
• Integrins
• Superoxides
• Hydrogen Peroxide

Topics

• Angiopoietin-Like Protein 4
• Angiopoietins (genetics, metabolism)
• Animals
• Anoikis
• Carcinoma, Basal Cell (genetics, metabolism, pathology)
• Carcinoma, Squamous Cell (genetics, metabolism, pathology)
• Cell Line
• Cell Line, Tumor
• Cell Survival
• Female
• Humans
• Hydrogen Peroxide (metabolism)
• Immunoblotting
• Integrins (metabolism)
• Intracellular Space (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Nude
• Neoplasms (genetics, metabolism, pathology)
• Protein Binding
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Superoxides (metabolism)
• Transplantation, Heterologous