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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Antibiotics, Antineoplastic / therapeutic use
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Apoptosis* / drug effects
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Cell Division / drug effects
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Cell Survival / drug effects
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Disease Progression
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Drug Resistance, Neoplasm*
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Eukaryotic Initiation Factor-4E / genetics
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Eukaryotic Initiation Factor-4E / metabolism*
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Eukaryotic Initiation Factor-4G / metabolism
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Female
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Lymphoma, B-Cell / drug therapy*
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Lymphoma, B-Cell / metabolism
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Lymphoma, B-Cell / pathology*
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Mice
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Mice, Inbred C57BL
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Neoplasm Transplantation
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Protein Kinase Inhibitors
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction* / drug effects
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Sirolimus / pharmacology
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Sirolimus / therapeutic use
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TOR Serine-Threonine Kinases
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antibiotics, Antineoplastic
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Eukaryotic Initiation Factor-4E
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Eukaryotic Initiation Factor-4G
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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Protein Kinases
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mTOR protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Sirolimus