RRC ID 67736
著者 Nishimura T, Nakata A, Chen X, Nishi K, Meguro-Horike M, Sasaki S, Kita K, Horike SI, Saitoh K, Kato K, Igarashi K, Murayama T, Kohno S, Takahashi C, Mukaida N, Yano S, Soga T, Tojo A, Gotoh N.
タイトル Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2.
ジャーナル Oncogene
Abstract 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.
巻・号 38(14)
ページ 2464-2481
公開日 2019-4-1
DOI 10.1038/s41388-018-0589-1
PII 10.1038/s41388-018-0589-1
PMID 30532069
PMC PMC6484769
MeSH Aminohydrolases / metabolism* Aminoimidazole Carboxamide / analogs & derivatives Aminoimidazole Carboxamide / metabolism Carcinogenesis / metabolism Carcinogenesis / pathology Cell Line Cell Line, Tumor Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / physiology* Folic Acid / metabolism Gefitinib / pharmacology* Gene Expression Regulation, Neoplastic / physiology HEK293 Cells Humans Lung Neoplasms / metabolism Lung Neoplasms / pathology Metabolic Networks and Pathways / physiology* Methylenetetrahydrofolate Dehydrogenase (NADP) / metabolism* 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 Purines / metabolism* Ribonucleotides / metabolism beta Catenin / metabolism
IF 7.971
リソース情報
遺伝子材料 pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)