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JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer
Wang, Huogang1,2,3; Hong, Bo1,3; Li, Xuemin1,3; Deng, Ke1,2,3; Li, Hong1,3; Lui, Vivian Wai Yan4; Lin, Wenchu1,3
2017-10-17
发表期刊ONCOTARGET
卷号8期号:49页码:86312-86324
摘要Small cell lung cancer (SCLC) is a clinically aggressive cancer with very poor prognosis. Amplification of MYC family genes and overexpression of Bcl-2 protein are common in SCLC, and they are likely therapeutic targets for SCLC. Previous clinical study showed that single agent targeting Bcl-2 with ABT-263 was of limited efficacy in SCLC. In this study, we demonstrated for the first time that co-targeting of N-Myc and Bcl-2 resulted in marked synergistic antitumor effects in MYCN-amplified SCLC. We found that MYCN-amplified SCLC cells were highly sensitive to a Bromodomain and Extra-Terminal domain ( BET) inhibitor JQ1, which was able to inhibit N-Myc protein expression. The inhibition of N-Myc by JQ1 induced the expression of Bim, and thereby sensitizing MYCN-amplified SCLC cells to ABT-263. The knockdown on Bim by siRNA reduced this JQ1/ABT-263 induced cell death. ABT-263 and JQ1 cotreatment in MYCN-amplified SCLC cells markedly disrupted Bim/Bcl-2 interaction, and prevented Bim's interaction with Mcl-1. Importantly, this JQ1/ABT-263 co-targeting substantially inhibited the growth of MYCN-amplified SCLC xenografts in vivo. Our study demonstrates a new JQ-1/ABT-263 co-targeting strategy that can be employed for MYCN-amplified SCLC with high efficacy.
文章类型Article
关键词Small Cell Lung Cancer N-myc Bcl-2 Jq1 Abt-263
WOS标题词Science & Technology ; Life Sciences & Biomedicine
资助者National Natural Science Foundation of China(81372214 ; Natural Science Foundation of Anhui Province(1608085MH179) ; Key Technologies R & D Programme of Anhui Province(1604a0802103) ; Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(2016FXCX006) ; 100-Talent Program of Chinese Academy of Sciences ; Research Grant Council, Hong Kong(17114814 ; School of Biomedical Sciences, Faculty of Medicine ; Chinese University of Hong Kong ; 81502632) ; 17121616 ; T12-401/13-R) ; National Natural Science Foundation of China(81372214 ; Natural Science Foundation of Anhui Province(1608085MH179) ; Key Technologies R & D Programme of Anhui Province(1604a0802103) ; Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(2016FXCX006) ; 100-Talent Program of Chinese Academy of Sciences ; Research Grant Council, Hong Kong(17114814 ; School of Biomedical Sciences, Faculty of Medicine ; Chinese University of Hong Kong ; 81502632) ; 17121616 ; T12-401/13-R)
DOI10.18632/oncotarget.21146
关键词[WOS]BET BROMODOMAINS ; TUMOR-GROWTH ; PROTEIN ; COMBINATION ; CARCINOMA ; TARGET ; STATE ; BRD4 ; EXPRESSION ; THERAPIES
收录类别SCI
语种英语
资助者National Natural Science Foundation of China(81372214 ; Natural Science Foundation of Anhui Province(1608085MH179) ; Key Technologies R & D Programme of Anhui Province(1604a0802103) ; Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(2016FXCX006) ; 100-Talent Program of Chinese Academy of Sciences ; Research Grant Council, Hong Kong(17114814 ; School of Biomedical Sciences, Faculty of Medicine ; Chinese University of Hong Kong ; 81502632) ; 17121616 ; T12-401/13-R) ; National Natural Science Foundation of China(81372214 ; Natural Science Foundation of Anhui Province(1608085MH179) ; Key Technologies R & D Programme of Anhui Province(1604a0802103) ; Major/Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology(2016FXCX006) ; 100-Talent Program of Chinese Academy of Sciences ; Research Grant Council, Hong Kong(17114814 ; School of Biomedical Sciences, Faculty of Medicine ; Chinese University of Hong Kong ; 81502632) ; 17121616 ; T12-401/13-R)
WOS研究方向Oncology ; Cell Biology
WOS类目Oncology ; Cell Biology
WOS记录号WOS:000413077800142
引用统计
文献类型期刊论文
条目标识符http://ir.hfcas.ac.cn:8080/handle/334002/33808
专题中科院强磁场科学中心
作者单位1.Chinese Acad Sci, High Magnet Field Lab, Hefei 230031, Anhui, Peoples R China
2.Univ Sci & Technol China, Hefei 230036, Anhui, Peoples R China
3.Chinese Acad Sci, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei Inst Phys Sci, Hefei 230031, Anhui, Peoples R China
4.Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Hong Kong, Hong Kong, Peoples R China
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Wang, Huogang,Hong, Bo,Li, Xuemin,et al. JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer[J]. ONCOTARGET,2017,8(49):86312-86324.
APA Wang, Huogang.,Hong, Bo.,Li, Xuemin.,Deng, Ke.,Li, Hong.,...&Lin, Wenchu.(2017).JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer.ONCOTARGET,8(49),86312-86324.
MLA Wang, Huogang,et al."JQ1 synergizes with the Bcl-2 inhibitor ABT-263 against MYCN-amplified small cell lung cancer".ONCOTARGET 8.49(2017):86312-86324.
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