MYC Is a Major Determinant of Mitotic Cell Fate.
MYC Is a Major Determinant of Mitotic Cell Fate.
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DOI：
10.1016/j.ccell.2015.06.001
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发表时间：
2015-07-13
期刊：
影响因子：
50.3
通讯作者：
Taylor SS
中科院分区：
文献类型：
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作者：
Topham C;Tighe A;Ly P;Bennett A;Sloss O;Nelson L;Ridgway RA;Huels D;Littler S;Schandl C;Sun Y;Bechi B;Procter DJ;Sansom OJ;Cleveland DW;Taylor SS
紫杉醇和其他抗有丝分裂药物是一线化疗药物，但对患者有益的机制仍不清楚。在全基因组siRNA筛选后，我们确定了致癌转录因子Myc作为紫杉醇敏化剂。利用延时成像将有丝分裂行为与细胞命运相关联，我们发现Myc使细胞对有丝分裂阻滞剂和加速有丝分裂进程的药物敏感。Myc通过上调一组冗余的促凋亡BH 3-only蛋白和抑制促存活Bcl-xL来实现这一点。乳腺癌的基因表达分析表明，紫杉烷反应与Myc呈正相关，与Bcl-xL呈负相关。因此，药理学抑制Bcl-xL恢复Myc缺陷细胞的凋亡。这些结果为生物标志物和联合治疗提供了机会，可以增强传统和第二代抗有丝分裂药物。全基因组筛选显示Myc和Egr 1在有丝分裂停滞期间促进凋亡Myc上调BH 3-only蛋白并下调Bcl-xL Myc使肺癌、乳腺癌、卵巢癌和结肠癌细胞对抗有丝分裂药物敏感。显示Myc使癌细胞对有丝分裂阻断剂和通过调节凋亡网络的表达加速有丝分裂进程的试剂敏感。人乳腺癌中的紫杉烷应答与Myc水平正相关，与Bcl-xL水平负相关。
Taxol and other antimitotic agents are frontline chemotherapy agents but the mechanisms responsible for patient benefit remain unclear. Following a genome-wide siRNA screen, we identified the oncogenic transcription factor Myc as a taxol sensitizer. Using time-lapse imaging to correlate mitotic behavior with cell fate, we show that Myc sensitizes cells to mitotic blockers and agents that accelerate mitotic progression. Myc achieves this by upregulating a cluster of redundant pro-apoptotic BH3-only proteins and suppressing pro-survival Bcl-xL. Gene expression analysis of breast cancers indicates that taxane responses correlate positively with Myc and negatively with Bcl-xL. Accordingly, pharmacological inhibition of Bcl-xL restores apoptosis in Myc-deficient cells. These results open up opportunities for biomarkers and combination therapies that could enhance traditional and second-generation antimitotic agents. Genome-wide screen shows that Myc and Egr1 promote apoptosis during mitotic arrest Myc upregulates BH3-only proteins and downregulates Bcl-xL Myc sensitizes lung, breast, ovarian, and colon cancer cells to antimitotic drugs Pharmacological inhibition of Bcl-xL restores apoptosis in Myc-low cells Topham et al. show that Myc sensitizes cancer cells to mitotic blockers and agents that accelerate mitotic progression by regulating the expression of an apoptotic network. Taxane responses in human breast cancers correlate positively with the Myc level and negatively with the Bcl-xL level.