title: Bcl-xL promotes metastasis independent of its anti-apoptotic activity.
abstract: Bcl-xL suppresses mitochondria-mediated apoptosis and is frequently overexpressed in cancer to promote cancer cell survival. Bcl-xL also promotes metastasis. However, it is unclear whether this metastatic function is dependent on its anti-apoptotic activity in the mitochondria. Here we demonstrate that Bcl-xL promotes metastasis independent of its anti-apoptotic activity. We show that apoptosis-defective Bcl-xL mutants and an engineered Bcl-xL targeted to the nucleus promote epithelial-mesenchymal transition, migration, invasion and stemness in pancreatic neuroendocrine tumour (panNET) and breast cancer cell lines. However, Bcl-xL proteins targeted to the mitochondria or outside of the nucleus do not have these functions. We confirm our findings in spontaneous and xenograft mouse models. Furthermore, Bcl-xL exerts metastatic function through epigenetic modification of the TGFβ promoter to increase TGFβ signalling. Consistent with these findings, we detect nuclear Bcl-xL in human metastatic panNETs. Taken together, the metastatic function of Bcl-xL is independent of its anti-apoptotic activity and its residence in the mitochondria.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Choi
authors.affiliation: Division of Biostatistics and Epidemiology, Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Tang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yuanzhang
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Shin
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Panarelli
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Yao-Tseng
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York 10065, USA.
authors.forename: Yi-Chieh Nancy
authors.initials: YN
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051020:bcl-X Protein