Analysis and regulation of parasitic metabolism by cancer cells harboring pathogenic mitochondrial DNA mutation

• Project/Area Number: 25430110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Shimane University
• Principal Investigator: Takenaga Keizo 島根大学, 医学部, 准教授 (80260256)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ミトコンドリアDNA / 病因性変異 / 肺がん / 転移 / 寄生性がん代謝 / ATP / 乳酸トランスポーター / エネルギー代謝 / グルコース代謝 / 低酸素 / 変異 / 活性酸素種 / 寄生性代謝 / 腫瘍

Outline of Final Research Achievements

We investigated the characteristics of mouse lung carcinoma P29mtB82M cells from the aspect of energy metabolism that produce a low level of ATP in vitro due to a frame-shift mutation in the mitochondrial ND6 gene and a missense mutation in the COI gene while show high tumor growth and metastatic potential. The results indicated that P29mtB82M cells produced a higher level of ATP in vivo through higher levels of glycolysis, lactate production via lactate transporter MCT4, parasitic metabolism, glucose uptake under hypoxic conditions, and glucose uptake via stimulation of angiogenesis. In addition, we found that knockdown of MCT4 resulted in cell death of P29mtB82M cells, implying the strategy to suppress mtDNA-regulated metastasis.

Research Products

• [Journal Article] Interleukin-33 enhances programmed oncosis of ST2L-positive low-metastatic cells in the tumour microenvironment of lung cancer. (2016)
  • Author(s): Akimoto M, Hayashi JI, Nakae S, Saito H, Takenaga K.
  • Journal Title: Cell Death Dis. Volume: 7 Issue: 1 Pages: e2057-e2057
  • DOI: 10.1038/cddis.2015.418
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction. (2015)
  • Author(s): Ochiya T, Takenaga K, Asagiri M, Nakano K, Satoh H, Watanabe T, Imajoh-Ohmi S, Endo H.
  • Journal Title: Mol Ther Methods Clin Dev Volume: 2 Pages: 15008-15008
  • DOI: 10.1038/mtm.2015.8
  • Peer Reviewed / Open Access
• [Journal Article] Anticancer Effect of Ginger Extract against Pancreatic Cancer Cells Mainly through Reactive Oxygen Species-Mediated Autotic Cell Death. (2015)
  • Author(s): Akimoto M, Iizuka M, Kanematsu R, Yoshida M, Takenaga K.
  • Journal Title: PLoS One Volume: 10 Issue: 5 Pages: e0126605-e0126605
  • DOI: 10.1371/journal.pone.0126605
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anticancer Effect of Ginger Extract Against Pancreatic Cancer Cells Mainly Through Reactive Oxygen Species-Mediated Autotic Cell Death. (2015)
  • Author(s): Akimoto M, Iizuka M, Kanematsu R, Yoshida M, Takenaga K.
  • Journal Title: PLoS ONE Volume: 未定
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Silencing of S100A4, a metastasis-associated protein, in endothelial cells inhibits tumor angiogenesis and growth. (2014)
  • Author(s): Ochiya T, Takenaga K, Endo H.
  • Journal Title: Angiogenesis Volume: 17 Issue: 1 Pages: 17-26
  • DOI: 10.1007/s10456-013-9372-7
  • Peer Reviewed
• [Journal Article] Transmitochondrial mice as models for primary prevention of diseases caused by mutation in the tRNA(Lys) gene. (2014)
  • Author(s): Shimizu A, Mito T, Hayashi C, Ogasawara E, Koba R, Negishi I, Takenaga K, Nakada K, Hayashi J
  • Journal Title: Proc Natl Acad Sci USA Volume: 111 Issue: 8 Pages: 3104-3109
  • DOI: 10.1073/pnas.1318109111
  • Peer Reviewed
• [Journal Article] An inhibitor of HIF-α subunit expression suppresses hypoxia-induced dedifferentiation of human NSCLC into cancer stem cell-like cells (2013)
  • Author(s): Akimoto M, Nagasawa H, Hori H, Uto Y, Honma Y, Takenaga K.
  • Journal Title: World J Med Genet Volume: 3(4) Issue: 4 Pages: 41-54
  • DOI: 10.5496/wjmg.v3.i4.41
  • Peer Reviewed
• [Journal Article] Polymorphic mutations in mouse mitochondrial DNA regulate a tumor phenotype. (2013)
  • Author(s): Takibuchi G, Imanishi H, Morimoto M, Ishikawa K, Nakada K, Toyama-Sorimachi N, Kikkawa Y, Takenaga K, Hayashi J
  • Journal Title: Mitochondrion Volume: 13 Issue: 6 Pages: 881-887
  • DOI: 10.1016/j.mito.2013.07.117
  • NAID: 120007130592
  • Peer Reviewed
• [Journal Article] Specific mtDNA mutations in mouse carcinoma cells suppress their tumor formation via activation of the host innate immune system. (2013)
  • Author(s): Imanishi H, Takibuchi G, Kobayashi T, Ishikawa K, Nakada K, Mori M, Kikkawa Y, Takenaga K, Toyama-Sorimachi N, Hayashi J
  • Journal Title: PLoS One Volume: 8 Issue: 9 Pages: e75981-e75981
  • DOI: 10.1371/journal.pone.0075981
  • NAID: 120007136806
  • Peer Reviewed
• [Presentation] HIF-2αはヒト膵がん細胞のTRAIL細胞やT細胞による細胞傷害に対する感受性をsurvivinを介して制御する (2015)
  • Author(s): 原嶋奈々江、秋本美穂、竹永啓三、原田守
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋（名古屋国際会議場）
  • Year and Date: 2015-10-10
• [Presentation] 膵がん細胞に対するアディポネクチン受容体アゴニストの抗腫瘍効果 (2015)
  • Author(s): 秋本美穂、竹永啓三
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋（名古屋国際会議場）
  • Year and Date: 2015-10-09
• [Presentation] 膵がん細胞に対する生姜抽出物のautosis誘導を介した抗腫瘍効果 (2015)
  • Author(s): 竹永啓三、秋本美穂
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋（名古屋国際会議場）
  • Year and Date: 2015-10-08
• [Presentation] IL-33は腫瘍微小環境下においてprogrammed oncosis耐性高転移性肺癌細胞を選別する (2015)
  • Author(s): 秋本美穂、竹永啓三
  • Organizer: 第13回がんとハイポキシア研究会
  • Place of Presentation: 三島（国立遺伝学研究所）
  • Year and Date: 2015-06-05
• [Presentation] 可溶性ST2は炎症性のがん微小環境を修飾し膵がんの増殖を抑制する (2014)
  • Author(s): 秋元美穂、竹永啓三
  • Organizer: 第12回がんとハイポキシア研究会
  • Place of Presentation: ホテルマリターレ創世佐賀（佐賀）
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] HIF-2αの阻害はヒト膵がん細胞のTRAIL感受性を増強する (2014)
  • Author(s): 原嶋奈々江、秋元美穂、竹永啓三、原田守
  • Organizer: 第12回がんとハイポキシア研究会
  • Place of Presentation: ホテルマリターレ創世佐賀（佐賀）
  • Year and Date: 2014-11-21 – 2014-11-22
• [Presentation] 可溶性ST2は炎症性のがん微小環境を修飾し膵臓がんの腫瘍血管新生と増殖を抑制する (2014)
  • Author(s): 秋元美穂、原田守，竹永啓三
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 間質細胞との共培養によるミトコンドリアDNA変異を有する肺がん細胞での解糖系と生存の促進 (2014)
  • Author(s): 竹永啓三、秋元美穂
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] HIF-2αの阻害はヒト膵がん細胞のTRAIL感受性を増強する (2014)
  • Author(s): 原嶋奈々江、波里瑤子、門馬浩行、秋元美穂、竹永啓三、原田守
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-09-13 – 2014-09-14
• [Presentation] 膵臓がん細胞に対する生姜抽出物の抗腫瘍効果 (2014)
  • Author(s): 兼松里衣、秋元美穂、竹永啓三
  • Organizer: 第61回日本生薬学会
  • Place of Presentation: 福岡大学（福岡）
  • Year and Date: 2014-09-13 – 2014-09-14
• [Presentation] Soluble ST2 inhibits tumor growth and metastasis of colon carcinoma cells by modulating inflammatory microenvironment. (2013)
  • Author(s): Akimoto M, Honma Y, Takenaga K.
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: （横浜）パシフィコ横浜
• [Presentation] 可溶性IL-33受容体sST2による炎症性 修飾を介した大腸がんの転移の抑制． (2013)
  • Author(s): 秋元美穂、竹永啓三
  • Organizer: 第22回日本がん転移学会学術集会
  • Place of Presentation: （松本）ブエナビスタ松本