Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Gastrointestinal Cancer Biology, International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Cancer Lett. 2021 Dec 28;523:29-42. doi: 10.1016/j.canlet.2021.09.007. Epub 2021 Sep 9.
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 PK-59 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.
癌细胞巧妙地适应其微环境中的能量代谢。由于血管生成不足和纤维化导致的营养剥夺是胰腺导管腺癌 (PDAC) 的主要特征；因此，PDAC 细胞必须内在地产生能量。然而，通过激活 Kras 突变来增强能量产生不足以解释 PDAC 细胞的代谢重排。在这里，我们研究了 PDAC 细胞在丝氨酸饥饿下代谢转变的分子机制。氨基酸分析显示，PDAC 患者血液中的所有必需氨基酸和大多数非必需氨基酸浓度降低。此外，PHGDH 高肿瘤的 PDAC 患者的血浆丝氨酸浓度明显高于 PHGDH 低肿瘤的患者。尽管 PHGDH 启动子超甲基化的 PK-59 细胞的生长和肿瘤发生在丝氨酸饥饿时显著降低，但在 PHGDH 启动子低甲基化的 PDAC 细胞系中，通过丝氨酸生物合成通过 PHGDH 诱导来维持这些活性。事实上，通过焦磷酸测序的 DNA 甲基化分析显示，PHGDH 启动子的甲基化状态与人类 PDAC 组织中 PHGDH 表达水平呈负相关。除了丝氨酸饥饿诱导 PHGDH 外，PDAC 细胞还通过 PGAM1 敲低导致 3-PG 积累，从而增强丝氨酸生物合成，从而在丝氨酸饥饿下增强 PDAC 细胞生长和肿瘤生长。然而，PHGDH 敲低在丝氨酸饥饿下有效抑制 PDAC 细胞生长和肿瘤生长。这些发现为通过抑制 PHGDH 靶向丝氨酸生物合成途径是消除营养剥夺微环境中 PDAC 细胞的有效治疗方法提供了证据。
