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Histidine catabolism is a major determinant of methotrexate sensitivity
Nature ( IF 50.5 ) Pub Date : 2018-07-01 , DOI: 10.1038/s41586-018-0316-7 Naama Kanarek 1, 2, 3, 4 , Heather R Keys 1 , Jason R Cantor 1, 2, 3, 4 , Caroline A Lewis 1 , Sze Ham Chan 1 , Tenzin Kunchok 1 , Monther Abu-Remaileh 1, 2, 3, 4 , Elizaveta Freinkman 1 , Lawrence D Schweitzer 4 , David M Sabatini 1, 2, 3, 4
Nature ( IF 50.5 ) Pub Date : 2018-07-01 , DOI: 10.1038/s41586-018-0316-7 Naama Kanarek 1, 2, 3, 4 , Heather R Keys 1 , Jason R Cantor 1, 2, 3, 4 , Caroline A Lewis 1 , Sze Ham Chan 1 , Tenzin Kunchok 1 , Monther Abu-Remaileh 1, 2, 3, 4 , Elizaveta Freinkman 1 , Lawrence D Schweitzer 4 , David M Sabatini 1, 2, 3, 4
Affiliation
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The chemotherapeutic drug methotrexate inhibits the enzyme dihydrofolate reductase1, which generates tetrahydrofolate, an essential cofactor in nucleotide synthesis2. Depletion of tetrahydrofolate causes cell death by suppressing DNA and RNA production3. Although methotrexate is widely used as an anticancer agent and is the subject of over a thousand ongoing clinical trials4, its high toxicity often leads to the premature termination of its use, which reduces its potential efficacy5. To identify genes that modulate the response of cancer cells to methotrexate, we performed a CRISPR–Cas9-based screen6,7. This screen yielded FTCD, which encodes an enzyme—formimidoyltransferase cyclodeaminase—that is required for the catabolism of the amino acid histidine8, a process that has not previously been linked to methotrexate sensitivity. In cultured cancer cells, depletion of several genes in the histidine degradation pathway markedly decreased sensitivity to methotrexate. Mechanistically, histidine catabolism drains the cellular pool of tetrahydrofolate, 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 leukaemia xenografts to methotrexate. The histidine degradation pathway markedly influences the sensitivity of cancer cells to methotrexate and may be exploited to improve methotrexate efficacy through a simple dietary intervention.Histidine metabolism influences the sensitivity of cancer cells to methotrexate, with mice bearing leukaemia xenografts showing increased response to the drug upon histidine supplementation.
中文翻译：
组氨酸分解代谢是甲氨蝶呤敏感性的主要决定因素
化疗药物甲氨蝶呤抑制酶二氢叶酸还原酶1，该酶产生四氢叶酸，这是核苷酸合成中的重要辅助因子2。四氢叶酸的消耗通过抑制 DNA 和 RNA 的产生导致细胞死亡。尽管甲氨蝶呤被广泛用作抗癌剂，并且是一千多项正在进行的临床试验的主题4，但其高毒性往往导致其使用过早终止，从而降低其潜在疗效5。为了识别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 6,7。该筛选产生了 FTCD，它编码一种酶——甲酰亚胺基转移酶环脱氨酶——这是氨基酸组氨酸分解代谢所必需的，该过程以前与甲氨蝶呤敏感性无关。在培养的癌细胞中，组氨酸降解途径中几个基因的消耗显着降低了对甲氨蝶呤的敏感性。从机制上讲，组氨酸分解代谢会排出细胞池中的四氢叶酸，这对甲氨蝶呤处理的细胞特别有害。此外，组氨酸分解代谢中限速酶的表达与癌细胞系中甲氨蝶呤的敏感性和患者的存活率有关。组氨酸的体内膳食补充剂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。组氨酸降解途径显着影响癌细胞对甲氨蝶呤的敏感性，并可通过简单的饮食干预来提高甲氨蝶呤疗效。
更新日期：2018-07-01
中文翻译：
组氨酸分解代谢是甲氨蝶呤敏感性的主要决定因素
化疗药物甲氨蝶呤抑制酶二氢叶酸还原酶1，该酶产生四氢叶酸，这是核苷酸合成中的重要辅助因子2。四氢叶酸的消耗通过抑制 DNA 和 RNA 的产生导致细胞死亡。尽管甲氨蝶呤被广泛用作抗癌剂，并且是一千多项正在进行的临床试验的主题4，但其高毒性往往导致其使用过早终止，从而降低其潜在疗效5。为了识别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 6,7。该筛选产生了 FTCD，它编码一种酶——甲酰亚胺基转移酶环脱氨酶——这是氨基酸组氨酸分解代谢所必需的，该过程以前与甲氨蝶呤敏感性无关。在培养的癌细胞中，组氨酸降解途径中几个基因的消耗显着降低了对甲氨蝶呤的敏感性。从机制上讲，组氨酸分解代谢会排出细胞池中的四氢叶酸，这对甲氨蝶呤处理的细胞特别有害。此外，组氨酸分解代谢中限速酶的表达与癌细胞系中甲氨蝶呤的敏感性和患者的存活率有关。组氨酸的体内膳食补充剂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。组氨酸降解途径显着影响癌细胞对甲氨蝶呤的敏感性，并可通过简单的饮食干预来提高甲氨蝶呤疗效。
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