Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR.
Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR.
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DOI：
10.1016/j.apsb.2021.08.025
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发表时间：
2022-03
影响因子：
14.5
通讯作者：
Zhang, Youwei
中科院分区：
文献类型：
--
作者：
Wang, Fangfang;Jin, Sora;Pozo, Franklin Mayca;Tian, Danmei;Tang, Xiyang;Dai, Yi;Yao, Xinsheng;Tang, Jinshan;Zhang, Youwei
DNA损伤反应（DDR）是一种高度保守的基因组监测机制，在化疗药物存在下保持细胞活力。因此，抑制DDR的小分子有望增强化疗的抗癌作用。通过最近的化学文库筛选，我们发现紫草素是一种抑制剂，可以强烈抑制来自不同来源的癌细胞系中各种化疗药物激活的DDR。在机制上，紫草素通过诱导ATR的专性相关蛋白ATR和ATR相互作用蛋白（ATRIP）的降解，抑制了共济失调毛细血管扩张突变（ATM）的激活，并在较小程度上抑制了DDR信号的两个主要上游调节因子ATM和rad3相关蛋白（ATR）的激活。由于DDR抑制作用，紫草素在细胞培养和小鼠模型中均增强了化疗药物的抗癌作用。ATRIP的降解依赖于蛋白酶体，而ATM的降解依赖于半胱天冬酶-和溶酶体-，而不是蛋白酶体。过表达ATM可显著减轻紫草素和化疗药物诱导的DDR抑制和细胞死亡。这些新发现揭示了紫草素是一种泛DDR抑制剂，并确定了ATM是决定紫草素化疗增敏作用的主要因素。我们的数据可能通过诱导ATM降解促进紫草素及其衍生物作为潜在的化疗增敏剂的发展。紫草素诱导共济失调毛细血管扩张突变（ATM）和atr相互作用蛋白（ATRIP）的降解，从而抑制DNA损伤反应（DDR），从而使癌细胞对化疗变得敏感。
DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation. Shikonin induces degradation of ataxia telangiectasia mutated (ATM) and ATR-interacting protein (ATRIP), resulting in the inhibition of the DNA damage response (DDR) and consequently the sensitization of cancer cells to chemotherapy.
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影响因子：
16
作者：
Liu S;Shiotani B;Lahiri M;Maréchal A;Tse A;Leung CC;Glover JN;Yang XH;Zou L
通讯作者：
Zou L
影响因子：
11.4
作者：
Uziel, T;Lerenthal, Y;Shiloh, Y
通讯作者：
Shiloh, Y
影响因子：
56.9
作者：
Lee, JH;Paull, TT
通讯作者：
Paull, TT
影响因子：
5.7
作者：
Subhash, Vinod Vijay;Tan, Shi Hui;Yong, Wei Peng
通讯作者：
Yong, Wei Peng
DOI：
10.1073/pnas.94.15.8021
发表时间：
1997-07-22
影响因子：
11.1
作者：
Zhang, N;Chen, P;Lavin, MF
通讯作者：
Lavin, MF