Bcl-2 attenuates anticancer agents-induced apoptosis by sustained activation of Akt/protein kinase B in U937 cells

Apoptosis. 2005 Dec;10(6):1333-43. doi: 10.1007/s10495-005-2763-5.

Abstract

Aberrant overexpression of antiapoptotic members of the Bcl-2 protein family contributes to resistance to anticancer therapeutic drugs. Thus, this protein represent attractive target for novel anticancer agents. In the present study, we determined the effect of the anti-apoptosis protein Bcl-2 on caspase-3 activation, PLC-gamma1 degradation and Akt activation during the various anticancer agents-induced apoptosis. Treatment with chrysin for 12 h produced morphological features of apoptosis in U937 cells, which was associated with caspase-3 activation and PLC-gamma1 degradation. Induction of apoptosis was also accompanied by down-regulation of XIAP and inactivation of Akt. Chrysin-induced caspase-3 activation, PLC-gamma1 degradation and apoptosis were significantly attenuated in Bcl-2 overexpressing U937/Bcl-2 cells. Ectopic expression of Bcl-2 appeared to inhibit ceramide-, and Akt specific inhibitor (SH-6)-induced apoptosis by sustained Akt activation. Thus, our findings imply that some of the biological functions of Bcl-2 may be attributed to their ability to inhibit anticancer agents-induced apoptosis through the sustained Akt activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Caspase 3 / metabolism
  • Ceramides / pharmacology
  • Chromones / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Genetic Vectors
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Kinetics
  • Morpholines / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • Time Factors
  • U937 Cells

Substances

  • Antineoplastic Agents
  • Ceramides
  • Chromones
  • Enzyme Inhibitors
  • Flavonoids
  • Inhibitor of Apoptosis Proteins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyruvate Dehydrogenase (Acetyl-Transferring) Kinase
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • chrysin
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Caspase 3