Elevated expression of the V-ATPase D2 subunit triggers increased energy metabolite levels in KrasG12D-driven cancer cells: YANG et al.

: Mutations of the Ras oncogene are frequently detected in human cancers. Among Ras-mediated tumorigenesis, Kras-driven cancers are the most dominant mutation types. Here, we investigated molecular markers related to the Kras mutation, which is involved in energy metabolism in Kras mutant-driven cancer. We first generated a knock-in KrasG12D cell line as a model. The genotype and phenotype of the Kras G12D -driven cells were first confirmed. Dramatically elevated metabolite characterization was observed in Kras G12D -driven cells compared with wild-type cells. Analysis of mitochondrial metabolite-related genes showed that two of the 84 genes in Kras G12D -driven cells differed from control cells by at least twofold. The messenger RNA and protein levels of ATP6V0D2 were significantly upregulated in Kras G12D -driven cells. Knockdown of ATP6V0D2 expression inhibited motility and invasion but did not affect the proliferation of Kras G12D -driven cells. We further investigated ATP6V0D2 expression in tumor tissue microarrays. ATP6V0D2 overexpression was observed in most carcinoma tissues, such as melanoma, pancreas, and kidney. Thus, we suggest that ATP6V0D2, as one of the V-ATPase (vacuolar-type H + -ATPase) subunit isoforms, may be a potential therapeutic target for Kras mutation cancer.