Abstract
The AKT oncogenes are amplified or AKT kinase activity is constitutively elevated in several types of human malignancy. We sought to determine whether AKT might play a role in the development of resistance to apoptosis induced by chemotherapy. We showed that ovarian cancer cells either overexpressing constitutively active Akt/AKT1 or containing AKT2 gene amplification were highly resistant to paclitaxel than cancer cells express low AKT levels. The Akt/AKT1 clones also contained higher levels of phospho-Bad protein than parental cells. Further, the complexes between the endogenous proapoptotic protein, Bad, and the anti-apoptotic protein, BC1-XL were undetectable in Akt/AKT1 clones. These results suggest that Akt/AKT1 expressed in these clones can phosphorylate Bad and prevent it from binding to Bcl-XL. Furthermore, overexpression of Akt/AKT1 can inhibit the release of cytochrome c induced by paclitaxel. Therefore, our findings provide evidence that aberrant expression or activation of AKT in cancer cells may confer resistance to paclitaxel.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / enzymology
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Adenocarcinoma / pathology*
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Antineoplastic Agents, Phytogenic / pharmacology*
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Apoptosis / genetics*
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Arabidopsis Proteins*
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Carrier Proteins / metabolism
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Caspases / metabolism
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Cytochrome c Group / metabolism
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Enzyme Induction
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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In Situ Nick-End Labeling
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Oncogenes*
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Ovarian Neoplasms / enzymology
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Ovarian Neoplasms / pathology*
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Paclitaxel / pharmacology*
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Phosphorylation
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Plant Proteins / biosynthesis
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Plant Proteins / genetics
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Plant Proteins / physiology*
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Potassium Channels / biosynthesis
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Potassium Channels / genetics
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Potassium Channels / physiology*
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Recombinant Fusion Proteins / metabolism
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Transfection
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Tumor Cells, Cultured / enzymology
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Tumor Cells, Cultured / pathology
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bcl-Associated Death Protein
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bcl-X Protein
Substances
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Antineoplastic Agents, Phytogenic
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Arabidopsis Proteins
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BAD protein, human
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BCL2L1 protein, human
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Carrier Proteins
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Cytochrome c Group
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Neoplasm Proteins
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Plant Proteins
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Potassium Channels
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Fusion Proteins
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bcl-Associated Death Protein
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bcl-X Protein
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AKT1 protein, Arabidopsis
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AKT1 protein, human
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AKT2 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Caspases
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Paclitaxel