Positive Feedback Regulation of Poly(ADP-ribose) Polymerase 1 and the DNA-PK Catalytic Subunit Affects the Sensitivity of Nasopharyngeal Carcinoma to Etoposide.
Positive Feedback Regulation of Poly(ADP-ribose) Polymerase 1 and the DNA-PK Catalytic Subunit Affects the Sensitivity of Nasopharyngeal Carcinoma to Etoposide.
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聚（ADP-核糖）聚合酶 1 和 DNA-PK 催化亚基的正反馈调节影响鼻咽癌对依托泊苷的敏感性。
DOI：
10.1021/acsomega.1c04379
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发表时间：
2022-01-25
期刊：
影响因子：
4.1
通讯作者：
Wu L
中科院分区：
文献类型：
--
作者：
Zhang L;Zhuang Y;Tu G;Li D;Fan Y;Ye S;Xu J;Zheng M;Wu Y;Wu L
依托泊苷(VP-16)用于治疗各种癌症，包括鼻咽癌(NPC)；然而，癌症通过促进DNA修复而对这种药物产生耐药性。DNA-PK(DNA-PKcs)催化亚基和多聚ADP-核糖聚合酶1(PARP1)介导了DNA损伤剂对鼻咽癌细胞的获得性耐药和低存活。DNA修复可以改变鼻咽癌细胞对DNA损伤剂的敏感性，这两种酶在体内共同作用于DNA损伤。因此，我们探讨了DNA-PKcs与PARP1之间的关系，可能通过调节VP-16作用后的DNA修复来影响鼻咽癌细胞的存活。我们进行了实时定量聚合酶链式反应、Western blotting和酶联免疫分析，发现DNA-PKcs基因敲除下调了PARP1和PAR的表达。相反，PARP1基因敲除降低了DNA-PKcs的活性，表明DNA-PKcs和PARP1在VP-16诱导的DNA修复中相互调节。此外，奥拉帕利布(PARP1抑制剂)和NU7441(DNA-PKcs抑制剂)在体内外均可使鼻咽癌细胞对VP-16增敏，提示奥拉帕利布、NU7441和DNA损伤剂联合治疗鼻咽癌可能是一种成功的治疗方案。
Etoposide (VP-16) is used for the treatment of various cancers, including nasopharyngeal carcinoma (NPC); however, cancers develop resistance to this agent by promoting DNA repair. The DNA-PK (DNA-PKcs) catalytic subunit and poly(ADP-ribose) polymerase 1 (PARP1) mediate acquired resistance and poor survival in NPC cells exposed to DNA damaging agents. DNA repair can alter the sensitivity of NPC cells to DNA damaging agents, and these two enzymes function concomitantly in response to DNA damage in vivo. Therefore, we explored the relationship between DNA-PKcs and PARP1, which may affect NPC cell survival by regulating DNA repair after VP-16 treatment. We performed quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunoassays and found that DNA-PKcs knockdown downregulated the PARP1 and PAR expression. Conversely, PARP1 knockdown reduced DNA-PKcs activity, indicating the mutual regulation between DNA-PKcs and PARP1 in VP-16-induced DNA repair. Moreover, a combination treatment with olaparib (a PARP1 inhibitor) and NU7441 (a DNA-PKcs inhibitor) sensitized NPC cells to VP-16 in vitro and in vivo, suggesting that the combined treatment of olaparib, NU7441, and a DNA-damaging agent may be a successful treatment regimen in patients with NPC.
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影响因子：
3.8
作者：
D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
影响因子：
8.8
作者：
通讯作者：
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影响因子：
8
作者：
Ariumi, Y;Masutani, M;Noda, M
通讯作者：
Noda, M
影响因子：
5.3
作者：
Douglas, Pauline;Cui, Xiaoping;Meek, Katheryn
通讯作者：
Meek, Katheryn
DOI：
10.1126/science.aam7344
发表时间：
2017-03-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lord CJ;Ashworth A
通讯作者：
Ashworth A