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

Research output: Contribution to journalArticlepeer-review

239 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 languageEnglish (US)
Pages (from-to)227-238
Number of pages12
JournalCancer Cell
Volume7
Issue number3
DOIs
StatePublished - Mar 2005

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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