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

Soyoung Choi,Laura H Tang,Nicole C Panarelli,Yi Li,Yao-Tseng Chen,Sandra J Shin,Yuanzhang Fang,Xuejun Jiang,Yi-Chieh Nancy Du,Zhengming Chen

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.

Highlights

Bcl-xL suppresses mitochondria-mediated apoptosis and is frequently overexpressed in cancer to promote cancer cell survival
Using a mouse model of spontaneous multistep tumorigenesis, RIP-Tag; RIP-tva, we have previously identified a novel function of Bcl-xL in promoting invasion and metastasis of pancreatic neuroendocrine tumour[12]
To examine whether the canonical anti-apoptotic function is required for Bcl-xL-mediated cell migration and metastasis, we first used Bax/Bak double knockout (DKO) mouse embryonic fibroblasts (MEFs), which are defective in mitochondria-mediated apoptosis

Summary

Introduction

Bcl-xL suppresses mitochondria-mediated apoptosis and is frequently overexpressed in cancer to promote cancer cell survival. It is unclear whether this metastatic function is dependent on its anti-apoptotic activity in the mitochondria. We demonstrate that Bcl-xL promotes metastasis independent of its anti-apoptotic activity. Bcl-xL targeted to the nucleus promote epithelial–mesenchymal transition, migration, invasion and stemness in pancreatic neuroendocrine tumour (panNET) and breast cancer cell lines. Bcl-xL exerts metastatic function through epigenetic modification of the TGFb promoter to increase TGFb 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

Methods

Results

Conclusion