Bioengineered microRNAs suppress lung cancer cell metabolism and proliferation through targeting of folate cycle

Abstract

Lung cancer remains as the leading cause of cancer deaths in the world. Ver recently, we have established a novel technology for the production of bioengineered miRNA agents for the study of cancer biology and new therapies. Using recombinant miRNA molecules produced and folded in living cells, we identified a number of the most effective miRNAs for the inhibition of non‐small cell lung cancer (NSCLC) cell proliferation, among which miR‐22‐3p, miR‐9‐5p and miR‐218‐5p are all predicted to interfere with folate cycle and one‐carbon metabolism. The serine hydroxymethyltransferase‐1 (SHMT‐1), a tumor biomarker and important enzyme in folate biotransformation, was verified as a new target for both miR‐9‐5p and miR‐218‐5p. The methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L) was proven to be regulated by miR‐9‐5p directly. Furthermore, both methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase‐2 (MTHFD2) were significantly suppressed by miR‐22‐3p in NSCLC cells. As determined by accurate LC‐MS/MS methods, folate metabolites and amino acid metabolome were altered remarkably by individual miRNAs in human NSCLC cells. Consequently, glycolysis rate and mitochondrial function were significantly inhibited in NSCLC cells treated with these miRNAs, accompanied by cell cycle arrest, ROS accumulation, NADP+/NADPH imbalance and other metabolic dysfunctions. In conclusion, our results demonstrated that bioengineered miR‐22‐3p, miR‐9‐5p, and miR‐218‐5p act on folate cycle to suppress NSCLC cell metabolic capacity and exhibit strong antiproliferation activities. These findings provide new insights into mechanistic actions of tumor suppressive miRNAs and development of novel therapeutic strategies.Support or Funding InformationThis study was supported by National Cancer Institute (grant No. R01CA225958) and National Institute of General Medical Sciences (R01GM113888), National Institutes of Health.