Metabolism-Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53-Mutant Colon Cancer.
Metabolism-Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53-Mutant Colon Cancer.
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基于代谢的分子亚型鉴于p53突变结肠癌的有效酮症治疗。
DOI：
10.1002/advs.202201992
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发表时间：
2022-10
期刊：
影响因子：
15.1
通讯作者：
Shi, Hanping
中科院分区：
文献类型：
--
作者：
Tang, Meng;Xu, Hui;Huang, Hongyan;Kuang, Hao;Wang, Chenxi;Li, Qinqin;Zhang, Xin;Ge, Yizhong;Song, Mengmeng;Zhang, Xi;Wang, Ziwen;Ma, Chaobing;Kang, Jinlin;Zhang, Wanfang;Wang, You;Zhang, Bo;Zhang, Xiaowei;Chen, Yongbing;Cong, Minghua;Melino, Gerry;Wang, Xiaobin;Zhou, Fuxiang;Sun, Qiang;Shi, Hanping
尽管靶向癌症代谢是一种有前途的治疗策略，但临床成功取决于准确的分子和代谢亚型。在这里，本研究报告了与结肠癌生酮治疗相关的两种基于代谢的分子亚型：糖酵解（糖酵解+/酮解-）和酮解（糖酵解+/酮解+），其表现为代谢酶和线粒体功能障碍的不同特征，以及体外和体内对含酮干预措施的不同反应。值得注意的是，在 p53 突变肿瘤中，糖酵解亚型能够在葡萄糖限制下转化为酮解亚型，从而对与酮解酶上调相关的生酮治疗产生抵抗，例如突变 p53 导致的 OXCT1。突变体 p53 的变构激活剂有效阻断重新连接的分子表达和重新编程的代谢，从而抑制肿瘤生长。研究结果强调了代谢亚型在指导结肠癌生酮治疗中的实用性，并确定突变型 p53 作为生酮治疗的合成致死靶标。确定了与结肠癌生酮治疗相关的两种基于代谢的分子亚型：糖酵解（糖酵解+/酮解-）和酮解（糖酵解+/酮解+），其表现为代谢酶和线粒体功能障碍的不同特征，以及体外和体内对含酮干预措施的不同反应。这些发现强调了代谢亚型在指导结肠癌生酮治疗中的实用性，并确定突变型 p53 作为生酮治疗的合成致死靶标。
Although targeting cancer metabolism is a promising therapeutic strategy, clinical success depends on accurate molecular and metabolic subtyping. Here, this study reports two metabolism‐based molecular subtypes associated with the ketogenic treatment of colon cancer: glycolytic (glycolysis+/ketolysis−) and ketolytic (glycolysis+/ketolysis+), which are manifested by distinct profiles of metabolic enzymes and mitochondrial dysfunction, and by different responses to ketone‐containing interventions in vitro and in vivo. Notably, the glycolytic subtype is able to be transformed into the ketolytic subtype in p53‐mutated tumors upon glucose limitation, rendering resistance to ketogenic therapy associated with upregulation of ketolytic enzymes, such as OXCT1 by mutant p53. The allosteric activator of mutant p53 effectively blocks the rewired molecular expression and the reprogrammed metabolism, leading to the suppression of tumor growth. The findings highlight the utility of metabolic subtyping to guide ketogenic therapy in colon cancer and identify mutant p53 as a synthetic lethality target for ketogenic treatment. Two metabolism‐based molecular subtypes associated with ketogenic treatment of colon cancer are identified: glycolytic (glycolysis+/ketolysis−) and ketolytic (glycolysis+/ketolysis+), which are manifested by distinct profiles of metabolic enzymes and mitochondrial dysfunction, and by different responses to ketone‐containing interventions in vitro and in vivo. The findings highlight the utility of metabolic subtyping to guide the ketogenic therapy in colon cancer and identify mutant p53 as a synthetic lethality target for ketogenic treatment.
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影响因子：
16.6
作者：
Goodwin J;Neugent ML;Lee SY;Choe JH;Choi H;Jenkins DMR;Ruthenborg RJ;Robinson MW;Jeong JY;Wake M;Abe H;Takeda N;Endo H;Inoue M;Xuan Z;Yoo H;Chen M;Ahn JM;Minna JD;Helke KL;Singh PK;Shackelford DB;Kim JW
通讯作者：
Kim JW
影响因子：
9
作者：
Liu, Kun;Li, Fangzhou;Zhao, Wenhui
通讯作者：
Zhao, Wenhui
影响因子：
5.8
作者：
Fumarola, Claudia;Petronini, Pier Giorgio;Alfieri, Roberta
通讯作者：
Alfieri, Roberta
DOI：
10.1073/pnas.1501605112
发表时间：
2015-08-11
影响因子：
11.1
作者：
Daemen, Anneleen;Peterson, David;Evangelista, Marie
通讯作者：
Evangelista, Marie
影响因子：
29
作者：
Angelin A;Gil-de-Gómez L;Dahiya S;Jiao J;Guo L;Levine MH;Wang Z;Quinn WJ 3rd;Kopinski PK;Wang L;Akimova T;Liu Y;Bhatti TR;Han R;Laskin BL;Baur JA;Blair IA;Wallace DC;Hancock WW;Beier UH
通讯作者：
Beier UH