Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.
Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.
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通过同时抑制NADPH氧化酶和谷胱甘肽的生物合成选择性地杀死含有突变RAS的癌细胞。
DOI：
10.1038/s41419-021-03473-6
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发表时间：
2021-02-16
影响因子：
9
通讯作者：
Lu W
中科院分区：
文献类型：
--
作者：
Liu M;Wang D;Luo Y;Hu L;Bi Y;Ji J;Huang H;Wang G;Zhu L;Ma J;Kim E;Luo CK;Abbruzzese JL;Li X;Yang VW;Li Z;Lu W
致癌性RAS是几种类型癌症发生和发展的关键驱动因素。然而，通过靶向RAS（特别是RASG12D和RASG12V）和相关下游途径的有效治疗策略迄今为止尚未成功。致癌RAS破坏的癌症患者的治疗仍然是目前未满足的临床需求。与癌症代谢中的主要作用一致，致癌RAS激活提高了产生活性氧（ROS）的NADPH氧化酶（NOX）活性和清除ROS的谷胱甘肽生物合成。在一定的阈值下，氧化应激和抗氧化能力的提高实现了更高水平的氧化还原平衡，癌细胞依赖于此获得生存和增殖的选择性优势。然而，这种突出的代谢特征可能会使癌细胞容易受到NOX活性和谷胱甘肽生物合成的同时抑制，这可能被用作一种新的治疗策略。在这份报告中，我们测试了这一假设，通过治疗HRASG12 V转化的卵巢上皮细胞，突变KRAS携带胰腺癌和结肠癌细胞的小鼠和人类的起源，以及癌症异种移植，与二苯基碘铵（DPI）和丁硫醚亚砜亚胺（BSO）的组合，抑制NOX活性和谷胱甘肽的生物合成，分别。我们的研究结果表明，同时靶向NOX和谷胱甘肽的生物合成诱导了一个高度有效的杀伤癌细胞窝藏致癌RAS。因此，我们的研究提供了一种新的策略，对RAS轴承癌症，值得进一步的机制和翻译的调查。
Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.
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影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
3.7
作者：
Gysin, S;Rickert, P;McMahon, M
通讯作者：
McMahon, M
影响因子：
64.5
作者：
Chio IIC;Jafarnejad SM;Ponz-Sarvise M;Park Y;Rivera K;Palm W;Wilson J;Sangar V;Hao Y;Öhlund D;Wright K;Filippini D;Lee EJ;Da Silva B;Schoepfer C;Wilkinson JE;Buscaglia JM;DeNicola GM;Tiriac H;Hammell M;Crawford HC;Schmidt EE;Thompson CB;Pappin DJ;Sonenberg N;Tuveson DA
通讯作者：
Tuveson DA
影响因子：
9.3
作者：
Lau, Alexandria;Villeneuve, Nicole F.;Sun, Zheng;Wong, Pak Kin;Zhang, Donna D.
通讯作者：
Zhang, Donna D.
影响因子：
50.3
作者：
Trachootham, Dunyaporn;Zhou, Yan;Huang, Peng
通讯作者：
Huang, Peng