Wendel, H. G., De Stanchina, E., Fridman, J. S., Malina, A., Ray, S., Kogan, S., Cordon-Cardo, C., Pelletier, J., Lowe, S. W. (March 2004) Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature, 428 (6980). pp. 332-7. ISSN 1476-4687 (Electronic)
Abstract
Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Antibiotics Antineoplastic pharmacology therapeutic use Apoptosis drug effects Cell Division drug effects Cell Survival drug effects Akt Disease Progression Drug Resistance, Neoplasm Eukaryotic Initiation Factor-4E/genetics/ metabolism Eukaryotic Initiation Factor-4G/metabolism Female Lymphoma, B-Cell/ drug therapy/metabolism/ pathology Mice Mice, Inbred C57BL Neoplasm Transplantation Protein Kinase Inhibitors Protein Kinases/metabolism Protein-Serine-Threonine Kinases Proto-Oncogene Proteins/antagonists & inhibitors/genetics/ metabolism Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-bcl-2/metabolism Signal Transduction/drug effects Sirolimus/pharmacology/therapeutic use Tumor Suppressor Protein p53/genetics/metabolism |
| Subjects: | diseases & disorders > cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis diseases & disorders > cancer > drugs and therapies |
| CSHL Authors: | |
| Communities: | CSHL labs > Lowe lab |
| Depositing User: | CSHL Librarian |
| Date: | 18 March 2004 |
| Date Deposited: | 17 Jan 2012 17:49 |
| Last Modified: | 17 Jan 2012 17:49 |
| URI: | https://repository.cshl.edu/id/eprint/22514 |
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