Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy
- Author(s)
- Tan, TT; Degenhardt, K; Nelson, DA; Beaudoin, B; Nieves-Neira, W; Bouillet, P; Villunger, A; Adams, JM; White, E;
- Details
- Publication Year 2005-03,Volume 7,Issue #3,Page 227-238
- Journal Title
- CANCER CELL
- Publication Type
- Journal Article
- 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.
- Publisher
- CELL PRESS
- Keywords
- FAMILY-MEMBER BIM; PROTEASOME INHIBITOR BORTEZOMIB; CYTOCHROME-C RELEASE; CANCER CELL-LINES; BCL-2 FAMILY; GROWTH-FACTOR; BH3-ONLY PROTEINS; KAPPA-B; BAX; PATHWAY
- Publisher's Version
- https://doi.org/10.1016/j.ccr.2005.02.008
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2005-03-01 12:00:00