Putting the rap on Akt.
The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.
University of Pennsylvania, Abramson Family Cancer Research Institute, 421 Curie Blvd, Room 450 BRB II/III, Philadelphia, PA 19104-6160, USA.
James E
JE
Thompson
Craig B
CB
Thompson
D017209:Apoptosis; D015971:Gene Expression Regulation, Enzymologic; D006019:Glycolysis; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; C494929:PTEN protein, human