Cancer cells often evade apoptosis through upregulation of anti-apoptotic proteins and/or downregulation of pro-apoptotic proteins. Bcl-xL, a negative regulator of mitochondria-mediated apoptosis, is frequently overexpressed in cancer cells. Bcl-xL has long been known for its function in regulating apoptosis during embryonic development and in pathological conditions. Any role that Bcl-xL might play in tumor metastasis has been ascribed to its anti-apoptotic function; i.e. Bcl-xL may increase metastasis by lending survival advantage to the tumor cells during the course of metastasis. However, we have demonstrated that Bcl-xL’s metastatic function is independent of its canonical anti-apoptotic activity and instead requires a novel nuclear function in cancer. We found that Bcl-xL promotes migration, even when cells are defective in mitochondria-mediated apoptosis. Consistently, Bcl-xL mutants lacking anti-apoptotic activity can still promote migration, induce epithelial-mesenchymal transition (EMT), upregulate TGFβ, and increase migration and invasion of pancreatic neuroendocrine tumor cells and breast cancer cells. Importantly, our data demonstrated that forcible localization of Bcl-xL outside the nucleus impairs its metastatic function.

As a mitochondrial membrane protein in healthy cells, Bcl-xL’s transmembrane domain prevents its nuclear import. This suggests that Bcl-xL enters the nucleus by an active nuclear transport. We hypothesized that unique transporters likely exist so as to transport this normally mitochondria membrane-bound Bcl-xL protein to the nucleus. By using immunoprecipitation in combination with mass spectrometry, we identified a novel interacting partner of Bcl-xL. We are investigating whether this protein transports Bcl-xL into the nucleus to promote metastasis.

Citation Format: Tiantian Zhang, Sha Li, Joseph Na, Soyoung Chi, George Zhang, Yi-Chieh Nancy Du. Bcl-xL promotes metastasis via a novel nuclear function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1123.