Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer
Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer
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DOI：
10.1016/j.canlet.2021.09.007
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发表时间：
2021-10-02
期刊：
影响因子：
9.7
通讯作者：
Ishimoto, Takatsugu
中科院分区：
文献类型：
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作者：
Itoyama, Rumi;Yasuda-Yoshihara, Noriko;Ishimoto, Takatsugu
癌细胞巧妙地使其能量代谢适应其微环境。胰腺导管腺癌(PDAC)的一个主要特征是由于血管减少和纤维化导致的营养缺乏，因此，PDAC细胞必须从本质上产生能量。然而，通过激活Kras突变来增强能量产生不足以解释PDAC细胞的代谢重连。在这里，我们研究了丝氨酸饥饿下PDAC细胞代谢改变的分子机制。氨基酸分析显示，PDAC患者血液中所有必需氨基酸和大部分非必需氨基酸的浓度均降低。此外，PHGDH值高的PDAC患者的血浆丝氨酸浓度显著高于PHGDH值低的患者。尽管丝氨酸饥饿显著降低了PHGDH启动子高甲基化的PK59细胞的生长和成瘤能力，但在PHGDH诱导的PDAC细胞系中，通过丝氨酸的生物合成维持了这些活性。事实上，焦磷酸测序的DNA甲基化分析表明，在人PDAC组织中，PHGDH启动子的甲基化状态与PHGDH的表达水平呈负相关。除了丝氨酸饥饿诱导的PHGDH外，PDAC细胞在丝氨酸饥饿条件下通过PGAM1基因敲除3-PG积累促进了丝氨酸的生物合成，从而促进了PDAC细胞的生长和肿瘤生长。然而，PHGDH基因敲除有效地抑制了丝氨酸饥饿下PDAC细胞的生长和肿瘤的生长。这些发现证明，通过抑制PHGDH来靶向丝氨酸生物合成途径是在营养缺乏的微环境中消除PDAC细胞的一种有效的治疗方法。
Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma (PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments.