Authors: | Wendel, H. G.; de Stanchina, E.; Fridman, J. S.; Malina, A.; Ray, S.; Kogan, S.; Cordon-Cardo, C.; Pelletier, J.; Lowe, S. W. |
Article Title: | Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy |
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. |
Keywords: | signal transduction; survival; protein kinase b; adolescent; cancer chemotherapy; controlled study; unclassified drug; oncoprotein; gene mutation; genetics; proto-oncogene proteins; disease course; doxorubicin; nonhuman; chemotherapy; antineoplastic agent; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; cell survival; cell division; protein bcl 2; apoptosis; genes; protein kinases; protein kinase inhibitor; embryo; animal model; genotype; cyclophosphamide; drug effect; drug resistance; pathology; drug resistance, neoplasm; enzyme inhibitor; protein serine threonine kinase; oncology; protein p53; cancer therapy; mice, inbred c57bl; carcinogenesis; c57bl mouse; animalia; protein kinase inhibitors; b cell lymphoma; lymphoma, b-cell; drug antagonism; tumors; protein-serine-threonine kinases; disease progression; mammalian target of rapamycin; drug response; proto-oncogene proteins c-akt; lymphoma; murinae; initiation factor 4e; tumor suppressor protein p53; tumor model; neoplasm transplantation; antibiotics, antineoplastic; antineoplastic antibiotic; drug sensitivity; medicine; protein kinase; proto-oncogene proteins c-bcl-2; rapamycin; sirolimus; mutations; eukaryotic initiation factor-4e; cancer transplantation; elongation factor; drug products; target of rapamycin kinase; initiation factor 4g; female; priority journal; article; elongation factor 4e; eukaryotic initiation factor-4g |
Journal Title: | Nature |
Volume: | 428 |
Issue: | 6980 |
ISSN: | 0028-0836 |
Publisher: | Nature Publishing Group |
Date Published: | 2004-03-18 |
Start Page: | 332 |
End Page: | 337 |
Language: | English |
DOI: | 10.1038/nature02369 |
PROVIDER: | scopus |
PUBMED: | 15029198 |
DOI/URL: | |
Notes: | Nature -- Cited By (since 1996):578 -- Export Date: 16 June 2014 -- CODEN: NATUA -- Source: Scopus |