The role of glutamine/Nrf2-enhanced PHGDH in Cadmium-induced lactate utilization

Cadmium (Cd) is a toxic heavy metal that is closely associated with the occurrence and progression of lung cancer. Our previous studies showed that Cd promoted lactate utilization and the expression of phosphoglycerate dehydrogenase (PHGDH), which is the key enzyme in serine biosynthesis. In this study, the role of PHGDH in Cd-induced lactate utilization was investigated. First, we found that PHGDH enhanced Monocarboxylate transporter 1 (MCT1) but not MCT4 in both A549 cells and tumor tissues formed by injection of siPHGDH-treated A549 cells in male BALB/c mice. Then, glutamine deprivation and transfection with siASCT2 (Alanine-Serine-Cysteine Transporter 2) revealed that glutamine was involved in Cd-induced Nrf2, PHGDH, glycolysis-related proteins, MCT1 and cell migration. Moreover, inhibition of Nrf2 with ML385 attenuated Cd-induced glutamine metabolism, PHGDH, MCT1, lactate production, and cell migration, while activation of Nrf2 with RTA-408 had the opposite effect. In addition, using RTA-408, ML385, glutamine addition and deprivation, we discovered that glutamine metabolism and Nrf2 interacted to enhance PHGDH and PHGDH-induced lactate utilization. Collectively, these findings suggest that PHGDH plays a crucial role in Cd-induced lactate utilization, and the mechanism underlies the interaction between glutamine and Nrf2. This study provides insights into the mechanism of Cd-related tumorigenesis and toxicity.