Cell fate determination in cisplatin resistance and chemosensitization.
Cell fate determination in cisplatin resistance and chemosensitization.
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DOI：
10.18632/oncotarget.8110
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Peng A
中科院分区：
文献类型：
--
作者：
Luong KV;Wang L;Roberts BJ;Wahl JK 3rd;Peng A
了解癌症治疗后细胞命运选择的决定将为癌症耐药性提供新的线索。在这项研究中，我们定量分析了顺铂对耐药UM-SCC-38头颈部癌细胞的个体命运选择。我们的研究揭示了UM-SCC-38细胞与对照、非致瘤性角质形成细胞HaCaT细胞相比，细胞命运选择的高度异质性。在UM-SCC-38和HaCaT细胞系中，大部分细胞死亡发生在没有有丝分裂进入的即刻间期，而UM-SCC-38细胞大部分通过检查点停滞或检查点滑移存活下来。有趣的是，检查点滑移主要发生在S晚期和G2期处理的细胞中，处于M期的细胞对顺铂敏感。此外，尽管顺铂耐药的有丝分裂进程总体上没有延迟，但延长有丝分裂与诱导有丝分裂中的细胞死亡有关。因此，这一发现建议使用顺铂和一种阻止有丝分裂退出的药物进行联合治疗。我们一直显示顺铂和蛋白酶体抑制剂MG132之间有很强的协同作用。最后，针对DNA损伤检查点使用ATR的抑制剂，而不是ATM，有效地使UM-SCC-38对顺铂治疗敏感。令人惊讶的是，检查点靶向消除了检查点停滞和检查点滑移，并在没有有丝分裂进入的情况下增加了间期细胞死亡的诱导。综上所述，我们的研究通过描绘顺铂治疗后细胞命运的决定，揭示了对化疗耐药性的新见解，并提出了潜在克服癌症耐药性的组合策略。
Understanding the determination of cell fate choices after cancer treatment will shed new light on cancer resistance. In this study, we quantitatively analyzed the individual cell fate choice in resistant UM-SCC-38 head and neck cancer cells exposed to cisplatin. Our study revealed a highly heterogeneous pattern of cell fate choices in UM-SCC-38 cells, in comparison to that of the control, non-tumorigenic keratinocyte HaCaT cells. In both UM-SCC-38 and HaCaT cell lines, the majority of cell death occurred during the immediate interphase without mitotic entry, whereas significant portions of UM-SCC-38 cells survived the treatment via either checkpoint arrest or checkpoint slippage. Interestingly, checkpoint slippage occurred predominantly in cells treated in late S and G2 phases, and cells in M-phase were hypersensitive to cisplatin. Moreover, although the cisplatin-resistant progression of mitosis exhibited no delay in general, prolonged mitosis was correlated with the induction of cell death in mitosis. The finding thus suggested a combinatorial treatment using cisplatin and an agent that blocks mitotic exit. Consistently, we showed a strong synergy between cisplatin and the proteasome inhibitor Mg132. Finally, targeting the DNA damage checkpoint using inhibitors of ATR, but not ATM, effectively sensitized UM-SCC-38 to cisplatin treatment. Surprisingly, checkpoint targeting eliminated both checkpoint arrest and checkpoint slippage, and augmented the induction of cell death in interphase without mitotic entry. Taken together, our study, by profiling cell fate determination after cisplatin treatment, reveals new insights into chemoresistance and suggests combinatorial strategies that potentially overcome cancer resistance.
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影响因子：
13.8
作者：
Flynn, Rachel Litman;Zou, Lee
通讯作者：
Zou, Lee
影响因子：
3.8
作者：
Clemenson, Celine;Marsolier-Kergoat, Marie-Claude
通讯作者：
Marsolier-Kergoat, Marie-Claude
DOI：
10.1002/hed.21198
发表时间：
2010-04
影响因子：
2.9
作者：
Brenner, J. Chad;Graham, Martin P.;Kumar, Bhavna;Saunders, Lindsay M.;Kupfer, Robbi;Lyons, Robert H.;Bradford, Carol R.;Carey, Thomas E.
通讯作者：
Carey, Thomas E.
DOI：
10.1042/bj20102162
发表时间：
2011-06-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Nam EA;Cortez D
通讯作者：
Cortez D
影响因子：
56.9
作者：
Orthwein, Alexandre;Fradet-Turcotte, Amelie;Durocher, Daniel
通讯作者：
Durocher, Daniel