The Epigenetic Regulator I-BET151 Induces BIM-Dependent Apoptosis and Cell Cycle Arrest of Human Melanoma Cells

被引:54
作者
Gallagher, Stuart J. [1 ]
Mijatov, Branka [1 ]
Gunatilake, Dilini [1 ]
Tiffen, Jessamy C. [1 ]
Gowrishankar, Kavitha [1 ]
Jin, Lei [1 ]
Pupo, Gulietta M. [2 ]
Cullinane, Carleen [3 ,4 ]
Prinjha, Rab K. [5 ]
Smithers, Nicholas [5 ]
McArthur, Grant A. [3 ,4 ]
Rizos, Helen [2 ]
Hersey, Peter [1 ,6 ]
机构
[1] Univ Sydney, Kolling Inst Med Res, Melanoma Res Grp, St Leonards, NSW 2065, Australia
[2] Univ Sydney, Westmead Hosp, Westmead Inst Canc Res, Westmead Millennium Inst, Westmead, NSW 2145, Australia
[3] Peter MacCallum Canc Ctr, Translat Res Lab, Melbourne, Vic, Australia
[4] Peter MacCallum Canc Ctr, Oncogen Signalling & Growth Control Program, Melbourne, Vic, Australia
[5] GlaxoSmithKline, Epinova Discovery Performance Unit, Stevenage, Herts, England
[6] Melanoma Inst Australia, Sydney, NSW, Australia
基金
英国医学研究理事会;
关键词
TRAIL-INDUCED APOPTOSIS; TUMOR-SUPPRESSOR; TARGETED THERAPY; KAPPA-B; RESISTANCE; INHIBITION; CHROMATIN; EXPRESSION; KINASE; CANCER;
D O I
10.1038/jid.2014.243
中图分类号
R75 [皮肤病学与性病学];
学科分类号
100206 ;
摘要
Epigenetic changes are widespread in melanoma and contribute to the pathogenic biology of this disease. In the present study, we show that I-BET151, which belongs to a new class of drugs that target the BET family of epigenetic "reader" proteins, inhibits melanoma growth in vivo and induced variable degrees of apoptosis in a panel of melanoma cells. Apoptosis was caspase dependent and associated with G1 cell cycle arrest. All melanoma cells tested had increased levels of the BH3 proapoptotic protein BIM, which appeared to be regulated by the BRD2 BET protein and to some extent by BRD3. In contrast, knockdown experiments indicated that inhibition of BRD4 was associated with decreased levels of BIM. Apoptosis was dependent on BIM in some but not all cell lines, indicating that other factors were determinants of apoptosis, such as downregulation of antiapoptotic proteins revealed in gene expression arrays. Cl cell cycle arrest appeared to be mediated by p21 and resulted from inhibition of the BRD4 protein. The activity of BET protein inhibitors appears independent of the BRAF and NRAS mutational status of melanoma, and further studies to assess their therapeutic role in melanoma are warranted.
引用
收藏
页码:2795 / 2805
页数:11
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