TY - JOUR
T1 - Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy
AU - Tan, Ting Ting
AU - Degenhardt, Kurt
AU - Nelson, Deirdre A.
AU - Beaudoin, Brian
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
Y1 - 2005/3
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.
AB - 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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U2 - 10.1016/j.ccr.2005.02.008
DO - 10.1016/j.ccr.2005.02.008
M3 - Article
C2 - 15766661
AN - SCOPUS:17644421083
SN - 1535-6108
VL - 7
SP - 227
EP - 238
JO - Cancer cell
JF - Cancer cell
IS - 3
ER -
