Responses in mantle cell lymphoma cells to SNS-032 depend on the biological context of each cell line.
SNS-032 is a potent inhibitor of cyclin-dependent kinases (Cdk) 2, 7, and 9 that regulate the cell cycle and transcription. Our studies in indolent primary chronic lymphocytic leukemia cells showed that SNS-032 inhibited transcription, diminished the antiapoptotic protein Mcl-1, and induced apoptosis. The present study focuses on evaluating this compound in four proliferating mantle cell lymphoma lines (Jeko-1, Granta 519, Mino, and SP-53). Consistent with its action against Cdk9 and Cdk7, SNS-032 inhibited the phosphorylation of RNA pol II in all four lines and blocked RNA synthesis. The transcripts and protein levels of short-lived proteins decreased, including cyclin D1 and Mcl-1. Cell growth was inhibited in a concentration-dependent manner in all lines. Apoptosis was induced in JeKo-1, Mino, and SP-53 cells without disrupting cell cycle distribution. However, apoptosis was limited in Granta cells; rather, there was a significant reduction of clonogenic survival. Small interfering RNA was used to specifically knock down Mcl-1 and cyclin D1 in JeKo-1 and Granta cells. Knocking down Mcl-1 induced significant apoptosis in Jeko-1 cells but not Granta cells. Reducing cyclin D1, rather than Mcl-1, was associated with loss of clonogenic survival in Granta cells. Thus, these results indicated that mantle cell lymphoma cell lines have distinct mechanisms sustaining their survival, and the mechanism of action of SNS-032 is dependent on the biological context of an individual line.
Chen
Rong
R
Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center and Graduate School of Biomedical Sciences, University of Texas Houston Health Science Center, Houston, Texas 77030, USA.
Chubb
Sherri
S
Cheng
Tiewei
T
Hawtin
Rachael E
RE
Gandhi
Varsha
V
Plunkett
William
W
D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010080:Oxazoles / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D012342:RNA, Small Nuclear / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014162:Transfection
C530104:CCND1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C484864:N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide; D010080:Oxazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D012334:RNA, Neoplasm; D012342:RNA, Small Nuclear; D013844:Thiazoles; D019938:Cyclin D1