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.
Researchers demonstrate that Bcl-xL promotes metastasis independent of its anti-apoptotic activity.
They 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 tumor (panNET) and breast cancer cell lines.
However, Bcl-xL proteins targeted to the mitochondria or outside of the nucleus do not have these functions. Authors confirm the 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, authors 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.