Bcl-xL promotes metastasis independent of its anti-apoptotic activity.

TitleBcl-xL promotes metastasis independent of its anti-apoptotic activity.
Publication TypeJournal Article
Year of Publication2016
AuthorsChoi S, Chen Z, Tang LH, Fang Y, Shin SJ, Panarelli NC, Chen Y-T, Li Y, Jiang X, Du Y-CNancy
JournalNat Commun
Volume7
Pagination10384
Date Published2016 Jan 20
ISSN2041-1723
KeywordsAnimals, Apoptosis, bcl-X Protein, Blotting, Western, Cell Line, Tumor, Cell Movement, Cell Survival, Chromatin Immunoprecipitation, Epithelial-Mesenchymal Transition, Humans, Immunohistochemistry, Immunoprecipitation, In Vitro Techniques, Mice, Neoplasm Metastasis
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.

DOI10.1038/ncomms10384
Alternate JournalNat Commun
PubMed ID26785948
PubMed Central IDPMC4735924
Grant ListR21 CA173348 / CA / NCI NIH HHS / United States
1R01GM113013 / GM / NIGMS NIH HHS / United States
1R01 CA166413 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
UL1TR000457 / TR / NCATS NIH HHS / United States
1R01CA124820 / CA / NCI NIH HHS / United States
R01 CA166413 / CA / NCI NIH HHS / United States
1R21CA173348-01A1 / CA / NCI NIH HHS / United States
R01 GM113013 / GM / NIGMS NIH HHS / United States
R01 CA124820 / CA / NCI NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
Related Faculty: 
Yi-Chieh (Nancy) Du, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
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