Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2

• Published in: Oncogene Vol. 38; no. 14; pp. 2464 - 2481
• Main Authors: Nishimura, Tatsunori, Nakata, Asuka, Chen, Xiaoxi, Nishi, Kurumi, Meguro-Horike, Makiko, Sasaki, Soichiro, Kita, Kenji, Horike, Shin-Ichi, Saitoh, Kaori, Kato, Keiko, Igarashi, Kaori, Murayama, Takahiko, Kohno, Susumu, Takahashi, Chiaki, Mukaida, Naofumi, Yano, Seiji, Soga, Tomoyoshi, Tojo, Arinobu, Gotoh, Noriko
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2019; Nature Publishing Group UK
• Subjects: Alkaloids; Aminohydrolases - metabolism; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - metabolism; Antineoplastic agents; beta Catenin - metabolism; Cancer; Cancer cells; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Line; Cell Line, Tumor; Dosage and administration; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - physiology; Drug therapy; Enzymes; Folic acid; Folic Acid - metabolism; Gefitinib; Gefitinib - pharmacology; Gene Expression Regulation, Neoplastic - physiology; Genetic aspects; HEK293 Cells; Humans; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Metabolic Networks and Pathways - physiology; Metabolism; Methylenetetrahydrofolate dehydrogenase; Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Multifunctional Enzymes - metabolism; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Prevention; Purines - metabolism; Recurrence (Disease); Ribonucleotides - metabolism; Stem cells; Targeted cancer therapy; Tumorigenesis; Tumors; β-Catenin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0589-1

Tumor recurrence is attributable to cancer stem-like cells (CSCs), the metabolic mechanisms of which currently remain obscure. Here, we uncovered the critical role of folate-mediated one-carbon (1C) metabolism involving mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) and its downstream purine synthesis pathway. MTHFD2 knockdown greatly reduced tumorigenesis and stem-like properties, which were associated with purine nucleotide deficiency, and caused marked accumulation of 5-aminoimidazole carboxamide ribonucleotide (AICAR)-the final intermediate of the purine synthesis pathway. Lung cancer cells with acquired resistance to the targeted drug gefitinib, caused by elevated expression of components of the β-catenin pathway, exhibited increased stem-like properties and enhanced expression of MTHFD2. MTHFD2 knockdown or treatment with AICAR reduced the stem-like properties and restored gefitinib sensitivity in these gefitinib-resistant cancer cells. Moreover, overexpression of MTHFD2 in gefitinib-sensitive lung cancer cells conferred resistance to gefitinib. 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. Because CSCs are dependent on MTHFD2, therapies targeting MTHFD2 may eradicate tumors and prevent recurrence.