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

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

doi:10.1038/ncomms10384

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

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

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

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.

Original language	English (US)
Article number	10384
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10384
State	Published - Jan 20 2016
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms10384

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@article{b82f48d361214218aa45c7c84bc671b6,

title = "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.",

author = "Soyoung Choi and Zhengming Chen and Tang, {Laura H.} and Yuanzhang Fang and Shin, {Sandra J.} and Panarelli, {Nicole C.} and Chen, {Yao Tseng} and Yi Li and Xuejun Jiang and Du, {Yi Chieh Nancy}",

note = "Funding Information: We thank Bu Jung Kim, Samantha Li, Sharon Pang, Leigh Selesner, Stephanie Azzopardi, Megan Wong and Christina Cherny in the Du laboratory for technical assistance; Harold Varmus, Jane Lyons and Aihao Ding for critical reading of the manuscript; Danny Huang for mouse database design and schematic; Diane L. Reidy and David S. Klimtra for the assistance on the research using human cancer samples; The Translational Research Program, especially Rob Kim, Bing He and Yifang Liu; Prashant Monian, Matthew Van Brocklin, Chris Harris, Joan Massague, Eileen White, Inna Serganova, Ronald Blasberg, David Andrews and Jae-Hyuck Shim for reagents; Ching-Hwa Sung and Juan Mendez for protocols; Mark Rubin, Timothy Hla and Ethel Cesarman for equipment and encouragement; Steven Merlin and Jason McCormick for cell sorting and training on flow cytometry; Sylvain Galvani for training on confocal microscope; Katia Manova-Todorova and Sho Fujisawa for imaging analysis; and the Weill Cornell Research Animal Resource Center. This work is partially supported by DOD grant W81XWH-13-1-0331 (to S.C. and Y.-C.N.D.), NIH grants 1R21CA173348-01A1 (to X.J. and Y.-C.N.D.), 1R01GM113013 (to X.J.), 1R01 CA166413 (to X.J.), UL1TR000457 (to Z.C.) and 1R01CA124820 (to Y.L.) and a Cycle for Survival grant (to X.J.).",

year = "2016",

month = jan,

day = "20",

doi = "10.1038/ncomms10384",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - Bcl-xL promotes metastasis independent of its anti-apoptotic activity

AU - Choi, Soyoung

AU - Chen, Zhengming

AU - Tang, Laura H.

AU - Fang, Yuanzhang

AU - Shin, Sandra J.

AU - Panarelli, Nicole C.

AU - Chen, Yao Tseng

AU - Li, Yi

AU - Jiang, Xuejun

AU - Du, Yi Chieh Nancy

N1 - Funding Information: We thank Bu Jung Kim, Samantha Li, Sharon Pang, Leigh Selesner, Stephanie Azzopardi, Megan Wong and Christina Cherny in the Du laboratory for technical assistance; Harold Varmus, Jane Lyons and Aihao Ding for critical reading of the manuscript; Danny Huang for mouse database design and schematic; Diane L. Reidy and David S. Klimtra for the assistance on the research using human cancer samples; The Translational Research Program, especially Rob Kim, Bing He and Yifang Liu; Prashant Monian, Matthew Van Brocklin, Chris Harris, Joan Massague, Eileen White, Inna Serganova, Ronald Blasberg, David Andrews and Jae-Hyuck Shim for reagents; Ching-Hwa Sung and Juan Mendez for protocols; Mark Rubin, Timothy Hla and Ethel Cesarman for equipment and encouragement; Steven Merlin and Jason McCormick for cell sorting and training on flow cytometry; Sylvain Galvani for training on confocal microscope; Katia Manova-Todorova and Sho Fujisawa for imaging analysis; and the Weill Cornell Research Animal Resource Center. This work is partially supported by DOD grant W81XWH-13-1-0331 (to S.C. and Y.-C.N.D.), NIH grants 1R21CA173348-01A1 (to X.J. and Y.-C.N.D.), 1R01GM113013 (to X.J.), 1R01 CA166413 (to X.J.), UL1TR000457 (to Z.C.) and 1R01CA124820 (to Y.L.) and a Cycle for Survival grant (to X.J.).

PY - 2016/1/20

Y1 - 2016/1/20

N2 - 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.

AB - 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.

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DO - 10.1038/ncomms10384

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VL - 7

JO - Nature Communications

JF - Nature Communications

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

Abstract

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