Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy Journal Article


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
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