Title | Bcl-xL promotes metastasis independent of its anti-apoptotic activity. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Choi S, Chen Z, Tang LH, Fang Y, Shin SJ, Panarelli NC, Chen Y-T, Li Y, Jiang X, Du Y-CNancy |
Journal | Nat Commun |
Volume | 7 |
Pagination | 10384 |
Date Published | 2016 Jan 20 |
ISSN | 2041-1723 |
Keywords | Animals, 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. |
DOI | 10.1038/ncomms10384 |
Alternate Journal | Nat Commun |
PubMed ID | 26785948 |
PubMed Central ID | PMC4735924 |
Grant List | R21 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.