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Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-κB-dependent process

Oncogene volume 22, pages 7108–7122 (2003)Cite this article

Abstract

Interactions between proteasome and cyclin-dependent kinase inhibitors have been examined in human leukemia cells in relation to induction of apoptosis. Simultaneous exposure (24 h) of U937 myelomonocytic leukemia cells to 100 nM flavopiridol and 300 nM MG-132 resulted in a marked increase in mitochondrial injury (cytochrome c, Smac/DIABLO release, loss of ΔΨm), caspase activation, and synergistic induction of cell death, accompanied by a marked decrease in clonogenic potential. Similar effects were observed with other proteasome inhibitors (e.g., Bortezomib (VELCADE™ bortezomib or injection), lactacystin, LLnL) and cyclin-dependent kinase inhibitors (e.g., roscovitine), as well as other leukemia cell types (e.g., HL-60, Jurkat, Raji). In U937 cells, synergistic interactions between MG-132 and flavopiridol were associated with multiple perturbations in expression/activation of signaling- and survival-related proteins, including downregulation of XIAP and Mcl-1, activation of JNK and p34cdc2, and diminished expression of p21CIP1. The lethal effects of MG-132/flavopiridol were not reduced in leukemic cells ectopically expressing Bcl-2, but were partially attenuated in cells ectopically expressing dominant-negative caspase-8 or CrmA. Flavopiridol/proteasome inhibitor-mediated lethality was also significantly diminished by agents and siRNA blocking JNK activation. Lastly, coadministration of MG-132 with flavopiridol resulted in diminished DNA binding of NF-κB. Notably, pharmacologic interruption of the NF-κB pathway (e.g., by BAY 11-7082, PDTC, or SN-50) or molecular dysregulation of NF-κB (i.e., in cells ectopically expressing an IκBα super-repressor) mimicked the actions of proteasome inhibitors in promoting flavopiridol-induced mitochondrial injury, JNK activation, and apoptosis. Together, these findings indicate that proteasome inhibitors strikingly lower the apoptotic threshold of leukemic cells exposed to pharmacologic CDK inhibitors, and suggest that interruption of the NF-κB cytoprotective pathway and JNK activation both play key roles in this phenomenon. They also raise the possibility that combining proteasome and CDK inhibitors could represent a novel antileukemic strategy.

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Acknowledgements

This work was supported by awards CA63753 and CA 93738 from the NIH and award 6045-03 from the Leukemia and Lymphoma Society of America.

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  1. Yun Dai and Mohamed Rahmani: These two authors contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298, VA, USA

    Yun Dai, Mohamed Rahmani & Steven Grant

  2. Department of Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298, VA, USA

    Steven Grant

  3. Department of Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond, 23298, VA, USA

    Steven Grant

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Correspondence to Steven Grant.

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Dai, Y., Rahmani, M. & Grant, S. Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-κB-dependent process. Oncogene 22, 7108–7122 (2003). https://doi.org/10.1038/sj.onc.1206863

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