Exogenous and Endogenous Sources of Serine Contribute to Colon Cancer Metabolism, Growth, and Resistance to 5-Fluorouracil.
Exogenous and Endogenous Sources of Serine Contribute to Colon Cancer Metabolism, Growth, and Resistance to 5-Fluorouracil.
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DOI：
10.1158/0008-5472.can-20-1541
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发表时间：
2021-05-01
期刊：
影响因子：
11.2
通讯作者：
Dannenberg AJ
中科院分区：
文献类型：
--
作者：
Montrose DC;Saha S;Foronda M;McNally EM;Chen J;Zhou XK;Ha T;Krumsiek J;Buyukozkan M;Verma A;Elemento O;Yantiss RK;Chen Q;Gross SS;Galluzzi L;Dow LE;Dannenberg AJ
丝氨酸是一种非必需氨基酸，由磷酸甘油酸脱氢酶(PHGDH)、磷酸丝氨酸转氨酶(PSAT1)和磷酸丝氨酸磷酸酶(PSPH)依次作用而成。丝氨酸生物合成增加发生在几种癌症中，并支持肿瘤的生长。此外，癌细胞可以利用外源性丝氨酸来促进其新陈代谢和增殖。在这里，我们测试了外源性和内源性丝氨酸来源对结直肠癌生物学的相对贡献。在小鼠肿瘤中，APC状态被认为是控制丝氨酸合成的基因表达的决定因素。在患者样本中，PSAT1在结直肠腺瘤和腺癌中均过表达。结合PSAT1基因缺失和外源性丝氨酸缺失，最大限度地抑制了结直肠癌细胞的增殖，并导致了严重的代谢缺陷，包括核苷酸合成减少。抑制丝氨酸合成增强了外源性丝氨酸去除后的转录变化以及与DNA损伤相关的变化。PSAT1的丢失和饮食中丝氨酸的去除是抑制结直肠癌移植瘤生长和增强5-氟尿嘧啶(5-FU)抗肿瘤活性所必需的。在体外限制内源性和外源性丝氨酸可增加5-FU诱导的细胞死亡、DNA损伤和代谢紊乱，这可能是观察到的抗肿瘤作用的原因。总之，我们的结果表明，内源性和外源性丝氨酸都有助于大肠癌的生长和对5-FU的耐药性。
Serine is a non-essential amino acid generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1), and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. Additionally, cancer cells can harness exogenous serine to enhance their metabolism and proliferation. Here we tested the relative contributions of exogenous and endogenous sources of serine on the biology of colorectal cancer (CRC). In murine tumors, Apc status was identified as a determinant of the expression of genes controlling serine synthesis. In patient samples, PSAT1 was overexpressed in both colorectal adenomas and adenocarcinomas. Combining genetic deletion of PSAT1 with exogenous serine deprivation maximally suppressed the proliferation of CRC cells and induced profound metabolic defects including diminished nucleotide production. Inhibition of serine synthesis enhanced the transcriptional changes following exogenous serine removal as well as alterations associated with DNA damage. Both loss of PSAT1 and removal of serine from the diet were necessary to suppress CRC xenograft growth and enhance the anti-tumor activity of 5-fluorouracil (5-FU). Restricting endogenous and exogenous serine in vitro augmented 5-FU induced cell death, DNA damage, and metabolic perturbations, likely accounting for the observed anti-tumor effect. Collectively, our results suggest that both endogenous and exogenous sources of serine contribute to CRC growth and resistance to 5-FU.