Cancer stem-like cells are maintained by the mitochondrial metabolic enzyme MTHFD2

An increase in the incidence and death rate from cancer has been noted worldwide, especially for lung cancer. Many patients with lung adenocarcinoma harbor mutations in the epidermal growth factor receptor (EGFR) and initially show a good response to molecular target drugs, such as gefitinib, which inhibits the tyrosine kinase of the body. ; EGFR. However, a recurrence inevitably occurs in a few years because of the acquired resistance to the drugs, which leads to a bad prognosis. Despite the development of new generations of molecular-targeted drugs, recurrence and acquired drug resistance remain problematic.

New evidence suggests that cancer stem cells (CSCs) are responsible for tumor recurrence and drug resistance. Tumor tissues include heterogeneous cell types including SCCs and their differentiated progeny as observed in normal tissues derived from tissue-specific stem cells. Most cancer treatments, such as conventional chemotherapy, radiotherapy and molecular drug targets, target fast-growing differentiated cancer cells, but not SCCs. It is thought that cancer cells with stem-like properties continue to survive after treatment, and that a fraction of these cells have the ability to divide again after years, resulting in recurrence. Thus, targeted therapies against SCCs and their daughter cells are important for tumor eradication; However, it is still an area of ​​unmet medical need. To establish such treatments, it is important to study the molecular mechanisms that determine how CHCs are maintained in cancerous tissues. Although it is thought that various metabolic pathways are activated in cancer cells, the specific metabolic mechanisms of SCCs remain largely unknown.

The carbon metabolism (1C) incorporates carbons as building blocks of purine and pyrimidine, which are used for DNA replication and RNA transcription, and therefore plays an important role in cell proliferation (Figure). In mitochondria, methylenetetrahydrofolate dehydrogenase (MTHFD2), an enzyme involved in 1C metabolism, is highly expressed in cancer cells, whereas it is barely in normal cells. MTHFD2 is necessary for the proliferation of cancer cells. Active MTHFD2 consumes 5-aminoimidazole carboxamide ribonucleotide (AICAR), an intermediate of the purine synthesis pathway, to produce IMP, a purine nucleotide.

We have discovered that it is essential to continuously consume AICAR and reduce its concentration in cancer cells to low levels for maintenance of SCCs. Active MTHFD2 is essential for this mechanism. Therefore, MTHFD2-induced mitochondrial 1C metabolism appears essential for the survival of SCCs and drug resistance, including gefitinib, through AICAR consumption, leading to intracellular pool depletion. d & # 39; AICAR. Since CSCs are dependent on MTHFD2, treatments targeting MTHFD2 can eliminate tumors and prevent recurrence.