Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy

Ting Ting Tan; Kurt Degenhardt; Deirdre A. Nelson; Brian Beaudoin; Wilberto Nieves-Neira; Philippe Bouillet; Andreas Villunger; Jerry M. Adams; Eileen White

doi:10.1016/j.ccr.2005.02.008

Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy

Ting Ting Tan, Kurt Degenhardt, Deirdre A. Nelson, Brian Beaudoin, Wilberto Nieves-Neira, Philippe Bouillet, Andreas Villunger, Jerry M. Adams, Eileen White^*

^*Corresponding author for this work

Obstetrics and Gynecology

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

261 Scopus citations

Abstract

Defective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.

Original language	English (US)
Pages (from-to)	227-238
Number of pages	12
Journal	Cancer cell
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2005.02.008
State	Published - Mar 2005

Funding

We thank Thomasina Sharkey for assistance with preparation of the manuscript. This work was supported by the Howard Hughes Medical Institute and a National Institutes of Health grant (R37 CA53370) to E.W. We thank Drs. David R. Plas, Peter Sabbatini, Eric Rubin, and Vassiliki Karantza-Wadsworth for providing reagents, and Dr. Andreas Strasser and members of the White laboratory for helpful advice.

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

UN SDGs

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

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10.1016/j.ccr.2005.02.008

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title = "Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy",

abstract = "Defective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.",

author = "Tan, {Ting Ting} and Kurt Degenhardt and Nelson, {Deirdre A.} and Brian Beaudoin and Wilberto Nieves-Neira and Philippe Bouillet and Andreas Villunger and Adams, {Jerry M.} and Eileen White",

note = "Funding Information: We thank Thomasina Sharkey for assistance with preparation of the manuscript. This work was supported by the Howard Hughes Medical Institute and a National Institutes of Health grant (R37 CA53370) to E.W. We thank Drs. David R. Plas, Peter Sabbatini, Eric Rubin, and Vassiliki Karantza-Wadsworth for providing reagents, and Dr. Andreas Strasser and members of the White laboratory for helpful advice. ",

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doi = "10.1016/j.ccr.2005.02.008",

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AU - Nieves-Neira, Wilberto

AU - Bouillet, Philippe

AU - Villunger, Andreas

AU - Adams, Jerry M.

AU - White, Eileen

N1 - Funding Information: We thank Thomasina Sharkey for assistance with preparation of the manuscript. This work was supported by the Howard Hughes Medical Institute and a National Institutes of Health grant (R37 CA53370) to E.W. We thank Drs. David R. Plas, Peter Sabbatini, Eric Rubin, and Vassiliki Karantza-Wadsworth for providing reagents, and Dr. Andreas Strasser and members of the White laboratory for helpful advice.

PY - 2005/3

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N2 - Defective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.

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Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy

Abstract

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ASJC Scopus subject areas

UN SDGs

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