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

Tatsunori Nishimura, Asuka Nakata, Xiaoxi Chen, Kurumi Nishi, Makiko Meguro-Horike, Soichiro Sasaki, Kenji Kita, Shin ichi Horike, Kaori Saitoh, Keiko Kato, Kaori Igarashi, Takahiko Murayama, Susumu Kohno, Chiaki Takahashi, Naofumi Mukaida, Seiji Yano, Tomoyoshi Soga, Arinobu Tojo, Noriko Gotoh

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
JournalOncogene
DOIs
Publication statusAccepted/In press - 2018 Jan 1

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Methylenetetrahydrofolate Dehydrogenase (NADP)
Enzymes
Neoplasms
Neoplastic Stem Cells
Lung Neoplasms
Purine Nucleotides
Recurrence
Catenins
purine
gefitinib
Folic Acid
Drug Resistance
Carcinogenesis
Carbon

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

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

In: Oncogene, 01.01.2018.

Research output: Contribution to journalArticle

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 2018, 'Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2', Oncogene. https://doi.org/10.1038/s41388-018-0589-1
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. / Cancer stem-like properties and gefitinib resistance are dependent on purine synthetic metabolism mediated by the mitochondrial enzyme MTHFD2. In: Oncogene. 2018.
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AU - Nishimura, Tatsunori

AU - Nakata, Asuka

AU - Chen, Xiaoxi

AU - Nishi, Kurumi

AU - Meguro-Horike, Makiko

AU - Sasaki, Soichiro

AU - Kita, Kenji

AU - Horike, Shin ichi

AU - Saitoh, Kaori

AU - Kato, Keiko

AU - Igarashi, Kaori

AU - Murayama, Takahiko

AU - Kohno, Susumu

AU - Takahashi, Chiaki

AU - Mukaida, Naofumi

AU - Yano, Seiji

AU - Soga, Tomoyoshi

AU - Tojo, Arinobu

AU - Gotoh, Noriko

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N2 - 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.

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