CDK Inhibitors Upregulate BH3-Only Proteins to Sensitize Human Myeloma Cells to BH3 Mimetic Therapies
In: Cancer research (Chicago, Ill.), Jg. 72 (2012), Heft 16, S. 4225-4237
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Zugriff:
BH3 mimetic drugs induce cell death by antagonizing the activity of antiapoptotic Bcl-2 family proteins. Cyclin-dependent kinase (CDK) inhibitors that function as transcriptional repressors downregulate the Bcl-2 family member Mcl-1 and increase the activity of selective BH3 mimetics that fail to target this protein. In this study, we determined whether CDK inhibitors potentiate the activity of pan-BH3 mimetics directly neutralizing Mcl-1. Specifically, we evaluated interactions between the prototypical pan-CDK inhibitor flavopiridol and the pan-BH3 mimetic obatoclax in multiple myeloma (MM) cells in which Mcl-1 is critical for survival. Coadministration of flavopiridol and obatoclax synergistically triggered apoptosis in both drug-naive and drug-resistant MM cells. Mechanistic investigations revealed that flavopiridol inhibited Mcl-1 transcription but increased transcription of Bim and its binding to Bcl-2/Bcl-xL. Obatoclax prevented Mcl-1 recovery and caused release of Bim from Bcl-2/Bcl-xL and Mcl-1, accompanied by activation of Bax/Bak. Whether administered singly or in combination with obatoclax, flavopiridol also induced upregulation of multiple BH3-only proteins, including BimEL, BimL, Noxa, and Bik/NBK. Notably, short hairpin RNA knockdown of Bim or Noxa abrogated lethality triggered by the flavopiridol/obatoclax combination in vitro and in vivo. Together, our findings show that CDK inhibition potentiates pan-BH3 mimetic activity through a cooperative mechanism involving upregulation of BH3-only proteins with coordinate downregulation of their antiapoptotic counterparts. These findings have immediate implications for the clinical trial design of BH3 mimetic-based therapies that are presently being studied intensively for the treatment of diverse hematopoietic malignancies, including lethal multiple myeloma. i.
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CDK Inhibitors Upregulate BH3-Only Proteins to Sensitize Human Myeloma Cells to BH3 Mimetic Therapies
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Autor/in / Beteiligte Person: | SHUANG, CHEN ; YUN, DAI ; RICHEY, Justin D ; LARSEN, Dustin G ; DENT, Paul ; ORLOWSKI, Robert Z ; GRANT, Steven ; PEI, Xin-Yan ; MYERS, Jennifer ; LI, WANG ; KRAMER, Lora B ; GARNETT, Mandy ; SCHWARTZ, Daniella M ; SU, Florence ; SIMMONS, Gary L |
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Zeitschrift: | Cancer research (Chicago, Ill.), Jg. 72 (2012), Heft 16, S. 4225-4237 |
Veröffentlichung: | Philadelphia, PA: American Association for Cancer Research, 2012 |
Medientyp: | academicJournal |
Umfang: | print, 50 ref |
ISSN: | 0008-5472 (print) |
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