title: Bcl-w promotes cell invasion by blocking the invasion-suppressing action of Bax.
abstract: The Bcl-2 family members are key regulators of cellular viability, either promoting or suppressing cell death. Recent reports have indicated that the pro-survival members (Bcl-w, Bcl-XL, and others) also enhance the migratory and invasive potentials of cancer cells, although the mechanisms underlying this phenomenon have yet to be adequately elucidated. Herein, by using human cancer cells and mouse embryonic fibroblasts, we demonstrate that Bcl-w functions in the mitochondria to increase the levels of reactive oxygen species (ROS), which subsequently stimulates the invasion-promoting signaling pathway. By way of contrast, Bax,a member of the multidomain pro-apoptotic group (Bax and Bak), was found to reduce ROS levels, thereby suppressing cell invasion. Analyses of the functional relationship between Bcl-w and Bax have shown that Bcl-w requires Bax for promoting cell invasion, whereas Bax suppresses cell invasion in a Bcl-win dependent manner. By using a Bcl-w mutant (Bcl-w/G94A) that was found not to bind to Bax, we have further determined that Bcl-w should bind to Bax to promote cell invasion. Overall, the results indicate that Bcl-w enhances cellular invasiveness by binding to Bax and subsequently blocking its invasion suppressing actions. Moreover, these functions of Bcl-w and Bax are mimicked by other pro-survival and pro-apoptotic members, such as Bcl-XL and Bak, respectively. We propose the balance between prosurvival and multidomain pro-apoptotic members as a novel determinant of cellular invasiveness.
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological & Medical Sciences, Seoul, Republic of Korea.
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Kim
authors.forename: Jongdoo
authors.initials: J
authors.lastname: Kim
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Won-Jae
authors.initials: WJ
authors.lastname: Lee
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Kang
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011506:Proteins / Q000032:analysis / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; C101155:Bcl2l2 protein, mouse; D011506:Proteins; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein