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

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.

Interleukin 8 mediates bcl‐xL‐induced enhancement of human melanoma cell dissemination and angiogenesis in a zebrafish xenograft model

“…Importantly, bcl-xL protein has recently been described as increasing invasiveness in a murine model of pancreatic neuroendocrine tumor and in breast cancer cell lines in mice, through enhancing epithelial-tomesenchimal transition. 44 Interestingly, in this model, bcl-xL protein might exert an epigenetic activity in the nucleus, leading to increased expression of transforming growth factor b, which is the mediator of bcl-xL-induced cell invasion. In our model, bcl-xL protein overexpression increases CXCL8 gene transcription enhancing NF-jB signaling by increasing the degradation of cytoplasmic inhibitor of NF-jB (IjB), as we previously demonstrated, 5 although we do not exclude a possible role for nuclear bcl-xL in enhancing cell invasion through CXCL8-dependent or -independent mechanisms.…”

“…Since the downregulation of Cxcl8 receptor expression did not counteract the capability of bcl‐xL overexpressing cells to invade zebrafish larvae, we focused our attention on the possible role of the autocrine CXCL8 pathway in the ability of bcl‐xL protein to enhance melanoma cell invasion in zebrafish embryos through CXCL8, demonstrating that the cell‐surface receptor CXCR2 is the mediator of the increased cell invasion induced by the bcl‐xL/CXCL8 axis. Importantly, bcl‐xL protein has recently been described as increasing invasiveness in a murine model of pancreatic neuroendocrine tumor and in breast cancer cell lines in mice, through enhancing epithelial‐to‐mesenchimal transition . Interestingly, in this model, bcl‐xL protein might exert an epigenetic activity in the nucleus, leading to increased expression of transforming growth factor β, which is the mediator of bcl‐xL‐induced cell invasion.…”

A fate worse than death: apoptosis as an oncogenic process

“…Bcl-2 family proteins have been implicated in a variety of non-apoptotic functions that may also impinge on tumourigenesis. These include regulation of calcium homeostasis, metastasis and autophagy -although how they regulate the latter remains controversial [97][98][99][100] .…”

Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

“…Generation of N134 and BON1-TGL cell lines has been described [1,14]. Human pancreatic L-glutamine, and penicillin/streptomycin.…”