Histidine catabolism is a major determinant of methotrexate sensitivity.
Histidine catabolism is a major determinant of methotrexate sensitivity.
复制标题
DOI：
10.1038/s41586-018-0316-7
复制
发表时间：
2018-07
期刊：
影响因子：
64.8
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Kanarek N;Keys HR;Cantor JR;Lewis CA;Chan SH;Kunchok T;Abu-Remaileh M;Freinkman E;Schweitzer LD;Sabatini DM
化疗药物甲氨蝶呤抑制酶DHFR（二氢叶酸还原酶），该酶产生四氢叶酸（THF），这是核苷酸合成中必不可少的辅因子。THF的消耗通过抑制DNA和RNA的产生而导致细胞死亡。虽然甲氨蝶呤被广泛用作抗癌剂，并且是一千多个正在进行的临床试验的主题，但其高毒性通常导致其使用过早终止，从而降低其潜在功效。为了鉴定调节癌细胞对甲氨蝶呤反应的基因，我们进行了基于CRISPR/Cas9的筛选。该筛选产生了FTCD，其编码氨基酸组氨酸的催化所需的酶（甲酰亚胺转移酶环脱氨酶），该过程先前与甲氨蝶呤敏感性无关。在培养的癌细胞中，组氨酸催化剂途径中多个基因的缺失显著降低了对甲氨蝶呤的敏感性。从机制上讲，组氨酸催化剂排出THF的细胞池，这对甲氨蝶呤处理的细胞特别有害。此外，组氨酸催化剂中限速酶的表达与癌细胞系中的甲氨蝶呤敏感性和患者的存活率相关。在体内饮食中补充组氨酸增加了通过组氨酸降解途径的通量，并增强了白血病异种移植物对甲氨蝶呤的敏感性。因此，组氨酸降解途径显著影响癌细胞对甲氨蝶呤的敏感性，并且可以通过简单的饮食干预来改善甲氨蝶呤的功效。
The chemotherapeutic drug methotrexate inhibits the enzyme DHFR (dihydrofolate reductase), which generates tetrahydrofolate (THF), an essential cofactor in nucleotide synthesis. Depletion of THF causes cell death by suppressing DNA and RNA production. While methotrexate is widely used as an anti-cancer agent and the subject of over a thousand ongoing clinical trials, its high toxicity often leads to the premature termination of its use, diminishing its potential efficacy. To identify genes that modulate the response of cancer cells to methotrexate, we performed a CRISPR/Cas9-based screen. This screen yielded FTCD, which encodes an enzyme (formimidoyltransferase cyclodeaminase) needed for the catabolism of the amino acid histidine, a process not previously linked to methotrexate sensitivity. In cultured cancer cells, depletion of multiple genes in the histidine catabolism pathway dramatically decreased sensitivity to methotrexate. Mechanistically, histidine catabolism drains the cellular pool of THF, which is particularly detrimental to methotrexate-treated cells. Moreover, expression of the rate-limiting enzyme in histidine catabolism is associated with methotrexate sensitivity in cancer cell lines and with survival rate in patients. In vivo dietary supplementation of histidine increased flux through the histidine degradation pathway and enhanced the sensitivity of leukemia xenografts to methotrexate. Thus, the histidine degradation pathway significantly influences the sensitivity of cancer cells to methotrexate and may be exploited to improve methotrexate efficacy through a simple dietary intervention.
登录
查看更多内容
癌细胞对葡萄糖限制和双胍类药物敏感性的代谢决定因素。
影响因子：
64.8
作者：
Birsoy, Kivanc;Possemato, Richard;Lorbeer, Franziska K.;Bayraktar, Erol C.;Thiru, Prathapan;Yucel, Burcu;Wang, Tim;Chen, Walter W.;Clish, Clary B.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
3
作者：
Yu C;Zavaljevski N;Desai V;Johnson S;Stevens FJ;Reifman J
通讯作者：
Reifman J
影响因子：
14.9
作者：
Allen F;Pon A;Wilson M;Greiner R;Wishart D
通讯作者：
Wishart D
DOI：
10.1634/theoncologist.2015-0164
发表时间：
2016-12
期刊：
The oncologist
影响因子：
--
作者：
Howard SC;McCormick J;Pui CH;Buddington RK;Harvey RD
通讯作者：
Harvey RD
DOI：
10.1073/pnas.84.20.7154
发表时间：
1987-10-01
影响因子：
11.1
作者：
ASSARAF, YG;SCHIMKE, RT
通讯作者：
SCHIMKE, RT