Serine racemase enhances growth of colorectal cancer by producing pyruvate from serine
Serine racemase enhances growth of colorectal cancer by producing pyruvate from serine
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DOI：
10.1038/s42255-019-0156-2
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发表时间：
2020-01-01
影响因子：
20.8
通讯作者：
Morii, Eiichi
中科院分区：
文献类型：
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作者：
Ohshima, Kenji;Nojima, Satoshi;Morii, Eiichi
丝氨酸种族酶（SRR）不仅催化了种族化，还会催化L丝氨酸和D-丝氨酸的脱水，从而导致丙酮酸和氨的形成。尽管SRR活性在中枢神经系统中很重要，但SRR以前尚未与癌症代谢有关。在这里，我们表明SRR支持结直肠癌细胞的增殖。我们发现，与人结直肠癌标本中的非肿瘤性粘膜相比，在结直肠腺瘤和腺癌病变中SRR表达上调。 SRR介导的丝氨酸的脱水有助于结肠癌细胞中的丙酮酸池，增强增殖，保持线粒体质量并增加具有抗凋亡作用的基础活性氧的产生。此外，SRR通过维持细胞内乙酰-COA水平来促进组蛋白H3的乙酰化。抑制SRR会抑制小鼠结肠直肠肿瘤的生长，并增强5-氟尿嘧啶治疗的功效。我们的发现突出了一种以前未知的机制，种族主义酶支持癌细胞的生长，并表明SRR可能是结直肠癌治疗的分子靶标。
Serine racemase (SRR) catalyses not only the racemization but also the dehydration of L-serine and D-serine, resulting in the formation of pyruvate and ammonia. Although SRR activity is important in the central nervous system, SRR has not been linked to cancer metabolism before. Here we show that SRR supports proliferation of colorectal-cancer cells. We find that SRR expression is upregulated in colorectal adenoma and adenocarcinoma lesions compared with non-neoplastic mucosa in human colorectal-cancer specimens. SRR-mediated dehydration of serine contributes to the pyruvate pool in colon-cancer cells, enhances proliferation, maintains mitochondrial mass and increases basal reactive oxygen species production, which has antiapoptotic effects. Moreover, SRR promotes acetylation of histone H3 by maintaining intracellular acetyl-CoA levels. Inhibition of SRR suppresses growth of colorectal tumours in mice and augments the efficacy of 5-fluorouracil treatment. Our findings highlight a previously unknown mechanism through which a racemase supports cancer-cell growth and suggest that SRR might be a molecular target for colorectal-cancer therapy.