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 journalArticle

229 Citations (Scopus)

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
Externally publishedYes

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Paclitaxel
Apoptosis
Drug Therapy
Neoplasms
Mitogen-Activated Protein Kinases
Proteasome Inhibitors
Proteasome Endopeptidase Complex
Carcinogenesis
Bortezomib

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Tan, T. T., Degenhardt, K., Nelson, D. A., Beaudoin, B., Nieves-Neira, W., Bouillet, P., ... White, E. (2005). Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell, 7(3), 227-238. https://doi.org/10.1016/j.ccr.2005.02.008

Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. / Tan, Ting Ting; Degenhardt, Kurt; Nelson, Deirdre A.; Beaudoin, Brian; Nieves-Neira, Wilberto; Bouillet, Philippe; Villunger, Andreas; Adams, Jerry M.; White, Eileen.

In: Cancer Cell, Vol. 7, No. 3, 03.2005, p. 227-238.

Research output: Contribution to journalArticle

Tan, TT, Degenhardt, K, Nelson, DA, Beaudoin, B, Nieves-Neira, W, Bouillet, P, Villunger, A, Adams, JM & White, E 2005, 'Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy', Cancer Cell, vol. 7, no. 3, pp. 227-238. https://doi.org/10.1016/j.ccr.2005.02.008
Tan TT, Degenhardt K, Nelson DA, Beaudoin B, Nieves-Neira W, Bouillet P et al. Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. Cancer Cell. 2005 Mar;7(3):227-238. https://doi.org/10.1016/j.ccr.2005.02.008
Tan, Ting Ting ; Degenhardt, Kurt ; Nelson, Deirdre A. ; Beaudoin, Brian ; Nieves-Neira, Wilberto ; Bouillet, Philippe ; Villunger, Andreas ; Adams, Jerry M. ; White, Eileen. / Key roles of BIM-driven apoptosis in epithelial tumors and rational chemotherapy. In: Cancer Cell. 2005 ; Vol. 7, No. 3. pp. 227-238.
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