RESUMO
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.
Assuntos
Carcinoma Ductal Pancreático/patologia , Ácidos Glicéricos/metabolismo , Neoplasias Pancreáticas/patologia , Fosfoglicerato Desidrogenase/fisiologia , Serina/biossíntese , Animais , Linhagem Celular Tumoral , Ilhas de CpG , Metilação de DNA , Indução Enzimática , Humanos , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Mutase/fisiologiaRESUMO
Immune cell function is tightly regulated by cellular metabolism, which in turn is strongly linked to the nutrient availability in the microenvironment surrounding the cells. This link is critical for effector CD8+ T cells which, after activation, must migrate from nutrient-rich environments into nutrient-scarce regions such as the tumor microenvironment. Assessing how nutrient availability modulates the metabolism of effector CD8+ T cells is thus key for understanding how harsh environments may impair their proliferation and effector function. Here, we describe an approach to systematically study the impact of the nutrient microenvironment on the metabolism of effector CD8+ T cells, based on performing stable 13C isotope labeling measurements on in vitro-differentiated murine effector CD8+ T cells.