Abstract
Dependence on Bcl-2 proteins is a common feature of cancer cells and provides a therapeutic opportunity. ABT-737 is an antagonist of antiapoptotic Bcl-2 proteins and therefore is a good predictor of Bcl-x(L)/Bcl-2 dependence. Surprisingly, analysis of Mcl-1-dependent multiple myeloma cell lines revealed codependence on Bcl-2/Bcl-x(L) in half the cells tested. Codependence is not predicted by the expression level of antiapoptotic proteins, rather through interactions with Bim. Consistent with these findings, acquired resistance to ABT-737 results in loss of codependence through redistribution of Bim to Mcl-1. Overall, these results suggest that complex interactions, and not simply expression patterns of Bcl-2 proteins, need to be investigated to understand Bcl-2 dependence and how to better use agents, such as ABT-737.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis Regulatory Proteins / physiology*
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Bcl-2-Like Protein 11
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Biphenyl Compounds / pharmacology
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Multiple Myeloma / genetics*
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols / pharmacology
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Piperazines / pharmacology
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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RNA, Small Interfering / pharmacology
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Sulfonamides / pharmacology
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Tissue Distribution
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
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bcl-X Protein / physiology*
Substances
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ABT-737
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L1 protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Biphenyl Compounds
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Sulfonamides
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bcl-X Protein