Year: 2016
Type: article
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.
Source: Nature Communications
DOI: 10.1038/ncomms10384
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1125781002, G252984251, G2676901002, G3619193012, G4119534169, G4610635183, G4931377843, Mechanisms and Function of Autophagy in Cancer, G5850682332, RHAMMB PROMOTES LIVER-SPECIFIC METASTASIS OF PANCREATIC NEUROENDOCRINE TUMORS, G746461529, G8632625050, Autophagy in Pancreatic Neuroendocrine Tumor Growth and Metastasis, G9000192713, Cancer Center Support Grant
OpenAlex ID: W2336890914