Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.
Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.
复制标题
ATR的药理抑制可以通过非ATR独立的机制阻止自噬。
DOI：
10.1016/j.isci.2020.101668
复制
发表时间：
2020-11-20
期刊：
影响因子：
5.8
通讯作者：
Hammond EM
中科院分区：
文献类型：
--
作者：
Bowler E;Skwarska A;Wilson JD;Ramachandran S;Bolland H;Easton A;Ostheimer C;Hwang MS;Leszczynska KB;Conway SJ;Hammond EM
自从开发出有效的抑制剂以来，ATR激酶的抑制已经成为靶向癌症的治疗上有吸引力的手段，其现在处于临床测试中。我们研究了ATR抑制和食管癌细胞自噬过程之间的潜在联系，使用四种ATR抑制剂，包括两种临床试验。对药物ATR抑制剂的反应与遗传系统进行了比较，以研究所观察到的效应的ATR依赖性。发现ATR抑制剂VX-970导致p62和LC 3-II的积累，表明自噬被阻断。p62的这种增加发生在转录后并且在所有测试的细胞系中。然而，我们的数据表明p62的积累以ATR非依赖性方式发生，而是对ATR抑制剂的脱靶反应。这项研究对药物ATR抑制的临床反应具有重要意义，在某些情况下，包括阻断自噬。使用VX-970抑制ATR导致p62积聚VX-970介导的p62积聚独立于ATR发生VX-970介导的p62积聚与阻断的自噬一致生物科学;生物化学;生物化学机制;癌症
Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy. Inhibition of ATR using VX-970 leads to an accumulation of p62 VX-970-mediated accumulation of p62 occurs independently of ATR VX-970-mediated accumulation of p62 is consistent with blocked autophagy Biological Sciences; Biochemistry; Biochemical Mechanism; Cancer
登录
查看更多内容
影响因子：
29
作者：
Kimmelman AC;White E
通讯作者：
White E
影响因子：
13.3
作者：
Hewitt G;Carroll B;Sarallah R;Correia-Melo C;Ogrodnik M;Nelson G;Otten EG;Manni D;Antrobus R;Morgan BA;von Zglinicki T;Jurk D;Seluanov A;Gorbunova V;Johansen T;Passos JF;Korolchuk VI
通讯作者：
Korolchuk VI
癌细胞中的MTORC1抑制在营养限制期间可防止谷氨酰胺溶解介导的凋亡。
影响因子：
16.6
作者：
Villar VH;Nguyen TL;Delcroix V;Terés S;Bouchecareilh M;Salin B;Bodineau C;Vacher P;Priault M;Soubeyran P;Durán RV
通讯作者：
Durán RV
对ATR抑制剂的临床前测试表明，对食管癌的标准疗法的反应得到了改善。
DOI：
10.1016/j.radonc.2016.10.023
发表时间：
2016-11
期刊：
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
影响因子：
--
作者：
Leszczynska KB;Dobrynin G;Leslie RE;Ient J;Boumelha AJ;Senra JM;Hawkins MA;Maughan T;Mukherjee S;Hammond EM
通讯作者：
Hammond EM
影响因子：
5.6
作者：
Yoshii SR;Mizushima N
通讯作者：
Mizushima N