Wang Yanbing, Sha Longze
State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
State Key Laboratory of Complex, Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China.
Invest New Drugs. 2025 Sep 12. doi: 10.1007/s10637-025-01581-0.
Serine metabolism plays a pivotal role in supporting the rapid proliferation of tumor cells, with PHGDH recognized as a key rate-limiting enzyme and therapeutic target. However, whether its antitumor effects rely exclusively on serine metabolism remains controversial. In this study, we compared the effects of PHGDH and PSPH inhibitors on serine metabolism and cell proliferation in the breast cancer cell lines HCC-70 and BT-20. While two PSPH inhibitors markedly reduced cellular serine M + 3 levels, they failed to effectively inhibit cell proliferation. In contrast, PHGDH inhibitors exhibited robust antiproliferative activity under both serine-deprived and serine-supplemented conditions. Furthermore, supplementation with α-ketoglutarate, a downstream metabolite of PHGDH, partially reversed this inhibitory effect. These findings indicate that the antitumor activity of PHGDH inhibition cannot be solely attributed to blockade of serine biosynthesis, but rather arises from the coordinated disruption of multiple metabolic pathways. This provides new insights into the potential of metabolic targeting strategies for cancer therapy.
丝氨酸代谢在支持肿瘤细胞的快速增殖中起关键作用，其中磷酸甘油酸脱氢酶（PHGDH）被认为是关键的限速酶和治疗靶点。然而，其抗肿瘤作用是否仅依赖于丝氨酸代谢仍存在争议。在本研究中，我们比较了PHGDH和磷酸丝氨酸磷酸酶（PSPH）抑制剂对乳腺癌细胞系HCC-70和BT-20中丝氨酸代谢和细胞增殖的影响。虽然两种PSPH抑制剂显著降低了细胞丝氨酸M+3水平，但它们未能有效抑制细胞增殖。相比之下，PHGDH抑制剂在丝氨酸缺乏和丝氨酸补充条件下均表现出强大的抗增殖活性。此外，添加PHGDH的下游代谢产物α-酮戊二酸可部分逆转这种抑制作用。这些发现表明，抑制PHGDH的抗肿瘤活性不能仅仅归因于丝氨酸生物合成的阻断，而是源于多种代谢途径的协同破坏。这为癌症治疗的代谢靶向策略的潜力提供了新的见解。
