Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy.
Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy.
复制标题
丝氨酸合成途径抑制与饮食丝氨酸和甘氨酸限制合作用于癌症治疗。
DOI：
10.1038/s41467-020-20223-y
复制
发表时间：
2021-01-14
影响因子：
16.6
通讯作者：
Vousden KH
中科院分区：
文献类型：
--
作者：
Tajan M;Hennequart M;Cheung EC;Zani F;Hock AK;Legrave N;Maddocks ODK;Ridgway RA;Athineos D;Suárez-Bonnet A;Ludwig RL;Novellasdemunt L;Angelis N;Li VSW;Vlachogiannis G;Valeri N;Mainolfi N;Suri V;Friedman A;Manfredi M;Blyth K;Sansom OJ;Vousden KH
许多肿瘤细胞表现出对外源丝氨酸和膳食丝氨酸和甘氨酸的依赖性，饥饿可以抑制这些癌症的生长并延长小鼠的生存期。然而，许多机制会促进对这种治疗方法的抵抗，包括增强丝氨酸从头合成途径（SSP）酶的表达或驱动增强丝氨酸合成的癌基因的激活。在这里，我们表明，抑制 PHGDH（SSP 的第一步）与丝氨酸和甘氨酸消耗协同抑制一碳代谢和癌症生长。在体外，抑制 PHGDH 与丝氨酸饥饿相结合会导致整体蛋白质合成缺陷，从而阻止 ATF-4 反应的激活，并更广泛地影响对氨基酸消耗的保护性应激反应。在体内，饮食和抑制剂的组合显示出对单独饮食或药物具有抗性的肿瘤的治疗功效，并有证据表明一碳可用性降低。然而，在完全耗尽可用丝氨酸后体外观察到的 ATF4 反应缺陷在小鼠中并未出现，其中膳食丝氨酸和甘氨酸耗尽以及用 PHGDH 抑制剂治疗降低了丝氨酸，但并未消除丝氨酸。我们的结果表明，抑制 PHGDH 将增强丝氨酸耗尽饮食的治疗效果。膳食丝氨酸和甘氨酸饥饿已成为癌症的潜在疗法。在这里，作者表明，抑制介导丝氨酸合成途径第一步的 PHGDH，可以提高小鼠异种移植模型中丝氨酸消耗饮食的治疗效果。
Many tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet. Dietary serine and glycine starvation has emerged as a potential therapy for cancer. Here, the authors show that inhibition of PHGDH, which mediates the first step in the serine synthesis pathway, improves the therapeutic efficacy of serine depletion diet in mouse xenograft models.
登录
查看更多内容
影响因子：
5.3
作者：
Lassot, I;Ségéral, E;Margottin-Goguet, F
通讯作者：
Margottin-Goguet, F
影响因子：
5.2
作者：
Jaeken, J;Detheux, M;VanSchaftingen, E
通讯作者：
VanSchaftingen, E
影响因子：
2.7
作者：
Mullarky, Edouard;Xu, Jiayi;Cantley, Lewis C.
通讯作者：
Cantley, Lewis C.
DOI：
10.1007/978-1-61779-815-3_6
发表时间：
2012
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Gracz AD;Puthoff BJ;Magness ST
通讯作者：
Magness ST
丝氨酸饥饿诱导癌细胞中的应激和p53依赖性代谢重塑。
影响因子：
64.8
作者：
Maddocks OD;Berkers CR;Mason SM;Zheng L;Blyth K;Gottlieb E;Vousden KH
通讯作者：
Vousden KH