Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation.

Abstract

The Bcl-2 antagonist ABT-737 targets Bcl-2/Bcl-xL but not Mcl-1, which may confer resistance to this novel agent. Here, we show that Mcl-1 down-regulation by the cyclin-dependent kinase (CDK) inhibitor roscovitine or Mcl-1-shRNA dramatically increases ABT-737 lethality in human leukemia cells. ABT-737 induces Bax conformational change but fails to activate Bak or trigger Bax translocation. Coadministration of roscovitine and ABT-737 untethers Bak from Mcl-1 and Bcl-xL, respectively, triggering Bak activation and Bax translocation. Studies employing Bax and/or Bak knockout mouse embryonic fibroblasts (MEFs) confirm that Bax is required for ABT-737+/-roscovitine lethality, whereas Bak is primarily involved in potentiation of ABT-737-induced apoptosis by Mcl-1 down-regulation. Ectopic Mcl-1 expression attenuates Bak activation and apoptosis by ABT-737+roscovitine, whereas cells overexpressing Bcl-2 or Bcl-xL remain fully sensitive. Finally, Mcl-1 knockout MEFs are extremely sensitive to Bak conformational change and apoptosis induced by ABT-737, effects that are not potentiated by roscovitine. Collectively, these findings suggest down-regulation of Mcl-1 by either CDK inhibitors or genetic approaches dramatically potentiate ABT-737 lethality through cooperative interactions at two distinct levels: unleashing of Bak from both Bcl-xL and Mcl-1 and simultaneous induction of Bak activation and Bax translocation. These findings provide a mechanistic basis for simultaneously targeting Mcl-1 and Bcl-2/Bcl-xL in leukemia.

• Authors: Shuang Chen, Yun Dai, Hisashi Harada, Paul Dent, Steven Grant
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 2 Pg. 782-91 (Jan 15 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17234790 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ABT-737
• BAK1 protein, human
• BAX protein, human
• BCL2L1 protein, human
• Biphenyl Compounds
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins
• Nitrophenols
• Piperazines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Purines
• Sulfonamides
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• bcl-X Protein
• Roscovitine
• Cyclin-Dependent Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Biphenyl Compounds (administration & dosage, pharmacology)
• Cyclin-Dependent Kinases (antagonists & inhibitors)
• Down-Regulation (drug effects)
• Drug Synergism
• HL-60 Cells
• Humans
• Jurkat Cells
• Leukemia (drug therapy, genetics, metabolism)
• Mice
• Mice, Knockout
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins (biosynthesis, genetics, metabolism)
• Nitrophenols (administration & dosage, pharmacology)
• Piperazines (administration & dosage, pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics, metabolism)
• Purines (administration & dosage, pharmacology)
• RNA Interference
• Roscovitine
• Sulfonamides (administration & dosage, pharmacology)
• U937 Cells
• bcl-2 Homologous Antagonist-Killer Protein (metabolism)
• bcl-2-Associated X Protein (metabolism)
• bcl-X Protein (metabolism)