The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1.
Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of malignant plasma cells with slow proliferative rate but enhanced survival. MM cells express multiple Bcl-2 family members, including Bcl-2, Bcl-XL, and Mcl-1, which are thought to play a key role in the survival and drug resistance of myeloma. The cyclin-dependent kinase inhibitor flavopiridol has antitumor activity against hematopoietic malignancies, including CLL, in which induction of apoptosis was associated with reduced expression of antiapoptotic proteins. Therefore, we sought to characterize the effect of flavopiridol on the proliferation and survival of myeloma cells and to define its mechanisms of action. Treatment of MM cell lines (8226, ANBL-6, ARP1, and OPM-2) with clinically achievable concentrations of flavopiridol resulted in rapid induction of apoptotic cell death that correlated temporally with the decline in Mcl-1 protein and mRNA levels. Levels of other antiapoptotic proteins did not change. Overexpression of Mcl-1 protected MM cells from flavopiridol-induced apoptosis. Additional analysis demonstrated that flavopiridol treatment resulted in a dose-dependent inhibition of phosphorylation of the RNA polymerase II COOH-terminal domain, thus blocking transcription elongation. These data indicate that Mcl-1 is an important target for flavopiridol-induced apoptosis of MM that occurs through inhibition of Mcl-1 mRNA transcription coupled with rapid protein degradation via the ubiquitin-proteasome pathway.
Gojo
Ivana
I
Greenebaum Cancer Center, University of Maryland Medical System, Baltimore, Maryland 21201, USA.
Zhang
Bin
B
Fenton
Robert G
RG
D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053667:Syndecans; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D005419:Flavonoids; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010880:Piperidines; D011509:Proteoglycans; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D053667:Syndecans; D051020:bcl-X Protein; C077990:alvocidib; D018844:Cyclin-Dependent Kinases; D020169:Caspases