Methionine Dependency of Cancer

项目摘要 30多年前，人们发现癌细胞显示出独特的代谢需求， 甲硫氨酸将它们与正常细胞分开。这种现象被称为“蛋氨酸 癌症的甲硫氨酸依赖性”或“癌症的甲硫氨酸敏感性”，并描述了 当蛋氨酸被其直接代谢前体同型半胱氨酸取代时，癌细胞中的蛋氨酸会发生变化。而 非致瘤细胞在同型半胱氨酸培养基中以正常速率增殖，绝大多数 当在同型半胱氨酸中培养时， 条件虽然高半胱氨酸向甲硫氨酸的转化在癌细胞中没有缺陷，但这些缺陷在癌细胞中并不存在。 生长条件似乎减少了通过一碳循环的通量，这似乎主要是 影响癌细胞生长。通过甲硫氨酸代谢对高代谢通量的依赖是 也在实体瘤和白血病中观察到。而甲硫氨酸敏感现象 癌症有巨大的治疗潜力，但很难充分减少蛋氨酸 在患者中，仅通过饮食限制就可以触发肿瘤消退。因此， 了解控制癌症的蛋氨酸依赖性的潜在机制。我们 因此，对NCI的挑衅性问题11（通过什么机制饮食和 营养干预影响对癌症治疗的反应？）并致力于了解分子 触发癌症的甲硫氨酸敏感性的机制，并发现 通过降低蛋氨酸的可用性而增强。

Project Summary Over 30 years ago it was discovered that cancer cells show a unique metabolic requirement for methionine that separates them from normal cells. This phenomenon is called “methionine dependence of cancer” or “methionine sensitivity of cancer” and describes the growth behavior of cancer cells when methionine is replaced with its immediate metabolic precursor homocysteine. While non-tumorigenic cells proliferate at normal rates in homocysteine medium, the overwhelming majority of cancer cells induces cell cycle arrest followed by apoptosis when cultured in homocysteine conditions. While conversion of homocysteine to methionine is not defective in cancer cells, these growth conditions appear to reduce the flux through the one-carbon cycle, which seems to primarily affect cancer cell growth. The dependence on high metabolic flux through methionine metabolism is also observed in solid tumors and leukemias. While the phenomenon of methionine sensitivity of cancer promises great therapeutic potential, it has been difficult to sufficiently reduce methionine availability in patients to trigger tumor regression through dietary restrictions alone. It is thus essential to understand the underlying mechanisms that govern methionine dependence of cancer. We therefore respond to the NCI’s provocative question 11 (Through what mechanisms do diet and nutritional interventions affect the response to cancer treatment?) and aim to understand molecular mechanisms that trigger methionine sensitivity of cancer, and discover treatment modalities that are enhanced by reduced methionine availability.