Bcl-xL, a negative regulator of mitochondria-mediated apoptosis, is frequently overexpressed in cancer to promote survival. Bcl-xL can also promote migration and/or metastasis. However, it is unclear whether this metastatic function is mediated via – or independent of – its anti-apoptotic activity and its residence at mitochondria. Here, we show that Bcl-xL promotes migration of cells defective in mitochondria-mediated apoptosis. Importantly, Bcl-xL mutants lacking anti-apoptotic activity still induce epithelial-mesenchymal transition (EMT), upregulate TGFβ, and increase metastasis of pancreatic neuroendocrine tumor (panNET) cells. In the RIP-Tag; RIP-tva mouse model, infection of pancreatic lesions with avian retroviruses carrying such Bcl-xL mutants promotes metastasis as potently as wild-type Bcl-xL does. Furthermore, engineered Bcl-xL targeted to the nucleus, but not mitochondria or outside of nucleus, promotes EMT and alters EMT-associated factors. In addition, nuclear Bcl-xL can be found in human metastatic panNET samples. Taken together, these data demonstrate that the metastatic function of Bcl-xL is independent of its anti-apoptotic activity and its residence at mitochondria.

Citation Format: Soyoung Choi, Zhengming Chen, Laura Tang, Yuanzhang Fang, Yi Li, Xuejun Jiang, Yi-Chieh Nancy Du. Beyond apoptosis, Bcl-xL in metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B33.