title: Overexpression of Akt/AKT can modulate chemotherapy-induced apoptosis.
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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109, USA.
authors.forename: C
authors.initials: C
authors.lastname: Page
authors.forename: H J
authors.initials: HJ
authors.lastname: Lin
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.forename: V P
authors.initials: VP
authors.lastname: Castle
authors.forename: G
authors.initials: G
authors.lastname: Nunez
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.forename: J
authors.initials: J
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics*; D029681:Arabidopsis Proteins; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004790:Enzyme Induction; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation; D010940:Plant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015221:Potassium Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000473:pathology; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D029681:Arabidopsis Proteins; C494819:BAD protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D003574:Cytochrome c Group; D009363:Neoplasm Proteins; D010940:Plant Proteins; D015221:Potassium Channels; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C074500:AKT1 protein, Arabidopsis; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D017239:Paclitaxel