Overexpression of Akt/AKT Can Modulate Chemotherapy-Induced Apoptosis

Anticancer Res. Jan-Feb 2000;20(1A):407-16.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / pathology*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / genetics*
  • Arabidopsis Proteins*
  • Carrier Proteins / metabolism
  • Caspases / metabolism
  • Cytochrome c Group / metabolism
  • Enzyme Induction
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • In Situ Nick-End Labeling
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Oncogenes*
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / pathology*
  • Paclitaxel / pharmacology*
  • Phosphorylation
  • Plant Proteins / biosynthesis
  • Plant Proteins / genetics
  • Plant Proteins / physiology*
  • Potassium Channels / biosynthesis
  • Potassium Channels / genetics
  • Potassium Channels / physiology*
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Tumor Cells, Cultured / enzymology
  • Tumor Cells, Cultured / pathology
  • bcl-Associated Death Protein
  • bcl-X Protein

Substances

  • Antineoplastic Agents, Phytogenic
  • Arabidopsis Proteins
  • BAD protein, human
  • BCL2L1 protein, human
  • Carrier Proteins
  • Cytochrome c Group
  • Neoplasm Proteins
  • Plant Proteins
  • Potassium Channels
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Fusion Proteins
  • bcl-Associated Death Protein
  • bcl-X Protein
  • AKT1 protein, Arabidopsis
  • AKT1 protein, human
  • AKT2 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspases
  • Paclitaxel