Abstract
The significance of mitochondrial metabolism in cancer cells has recently been gaining attention. Among other findings, One-carbon folate metabolism has been reported to be closely associated with cellular characteristics in cancer. To study molecular targets for efficient cancer therapy, we investigated the association between the expressions of genes that code enzymes involved in one-carbon metabolism and survival rate of patients with adenocarcinomas of the colorectum and lung. Patients with high expression of genes that control the metabolic cycle of tetrahydrofolate (THF) in mitochondria, SHMT2, MTHFD2, and ALDH1L2, have a shorter overall survival rate compared with patients with low expression of these genes. Our results revealed that these genes could be novel and more promising anticancer targets than dihydrofolate reductase (DHFR), the current target of drug therapy linked with folate metabolism, suggesting the rationale of drug discovery in cancer medicine.
Highlights
Folate is very important in bioorganic systems, it cannot be synthesized in humans[1]
We searched for better anticancer targets of C1 metabolism and performed correlation analysis between the expressions of genes involved in C1 metabolism and prognosis in patients with colorectal cancer (CRC) and lung adenocarcinoma (LA)
Our study unexpectedly revealed that the expression of dihydrofolate reductase (DHFR), the current anticancer target of folic acid metabolism, had no influence on the prognosis in patients with CRC or LA
Summary
Folate is very important in bioorganic systems, it cannot be synthesized in humans[1] It is acquired from food and converted to tetrahydrofolate [tetrahydrofolic acid (THF)], which is the reactant in the metabolic pathway of the folate cycle. Mitochondrial metabolism has received much attention as a potential target for cancer therapy[7,13]. If folate metabolism in the mitochondria is responsible for poor prognosis in cancer patients, the selective targeting of this pathway could be effective with few side effects because of the parallel pathway in the cytoplasm. We could identify other mitochondrial genes involved in C1 metabolism that are strongly associated with the prognosis in cancer patients, which we believe have the potential to be more efficient anticancer targets than DHFR, which is the anticancer target of folate metabolism
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