Furthermore, therapeutic strategies aiming to block the mitochondrial folate pathway in cancer should focus on MTHFD2, with MTHFD2L being unlikely to be involved in the development of chemoresistance to targeting of its mitochondrial isozyme.
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays a key role in one-carbon (1C) metabolism in human mitochondria, and its high expression correlates with poor survival of patients with various types of cancer.
Thus, MTHFD2-mediated mitochondrial 1C metabolism appears critical for cancer stem-like properties and resistance to drugs including gefitinib through consumption of AICAR, leading to depletion of the intracellular pool of AICAR.
MTHFD2 overexpression plays a key role in the progression of human cancers, and depletion of MTHFD2 has shown potential antitumor activities in several types of cancer.
MTHFD2 knockdown resulted in impaired cell migration and invasion into extracellular matrix as well as decreased the fraction of cells with a high CD44 expression, a marker of cancer stem cells.