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

Nat Commun. 2016 Jan 20;7:10384. doi: 10.1038/ncomms10384.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Movement / physiology*
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Chromatin Immunoprecipitation
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelial-Mesenchymal Transition / physiology
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • In Vitro Techniques
  • Mice
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism*

Substances

  • bcl-X Protein