文章：

MYC是胆碱代谢的正向调节因子，并抑制弥漫大B细胞淋巴瘤中依赖线粒体自噬的程序性坏死

MYC is a positive regulator of choline metabolism and impedes mitophagy-dependent necroptosis in diffuse large B-cell lymphoma

原文发布日期：2017-07-07

DOI: 10.1038/bcj.2017.61

类型: Original Article

开放获取: 是

英文摘要：

The activation of oncogenes can reprogram tumor cell metabolism. Here, in diffuse large B-cell lymphoma (DLBCL), serum metabolomic analysis revealed that oncogenic MYC could induce aberrant choline metabolism by transcriptionally activating the key enzyme phosphate cytidylyltransferase 1 choline-α (PCYT1A). In B-lymphoma cells, as a consequence of PCYT1A upregulation, MYC impeded lymphoma cells undergo a mitophagy-dependent necroptosis. In DLBCL patients, overexpression of PCYT1A was in parallel with an increase in tumor MYC, as well as a decrease in serum choline metabolite phosphatidylcholine levels and an International Prognostic Index, indicating intermediate–high or high risk. Both in vitro and in vivo, lipid-lowering alkaloid berberine (BBR) exhibited an anti-lymphoma activity through inhibiting MYC-driven downstream PCYT1A expression and inducing mitophagy-dependent necroptosis. Collectively, PCYT1A was upregulated by MYC, which resulted in the induction of aberrant choline metabolism and the inhibition of B-lymphoma cell necroptosis. Referred as a biomarker for DLBCL progression, PCYT1A can be targeted by BBR, providing a potential lipid-modifying strategy in treating MYC-High lymphoma.

摘要翻译： 

致癌基因的激活可重编程肿瘤细胞代谢。本研究发现在弥漫大B细胞淋巴瘤中，血清代谢组学分析显示致癌因子MYC可通过转录激活关键酶磷酸胞苷酰转移酶1胆碱-α（PCYT1A）诱导异常胆碱代谢。在B淋巴瘤细胞中，由于PCYT1A上调，MYC阻断了淋巴瘤细胞发生线粒体自噬依赖性坏死性凋亡。在DLBCL患者中，PCYT1A过表达与肿瘤MYC升高、血清胆碱代谢物磷脂酰胆碱水平降低以及国际预后指数（提示中高危或高危风险）呈平行关系。在体外和体内实验中，降脂生物碱小檗碱（BBR）均通过抑制MYC驱动的下游PCYT1A表达并诱导线粒体自噬依赖性坏死性凋亡，展现出抗淋巴瘤活性。综上，PCYT1A被MYC上调，导致异常胆碱代谢诱导和B淋巴瘤细胞坏死性凋亡抑制。作为DLBCL进展的生物标志物，PCYT1A可被小檗碱靶向干预，这为治疗MYC高表达淋巴瘤提供了一种潜在的脂质调节策略。

原文链接：

MYC is a positive regulator of choline metabolism and impedes mitophagy-dependent necroptosis in diffuse large B-cell lymphoma