Role of creatine cycle in cancer cachexia

• Project/Area Number: 19K19915
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 59010:Rehabilitation science-related
• Research Institution: Nara Medical University
• Principal Investigator: Goto Kei 奈良県立医科大学, 医学部, 研究員 (10469554)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: クレアチン・サイクル / CKB / mtCK / がん性悪液質 / がん性サルコペニア / ミトコンドリアCK / ホスホクレアチン / リン酸化経路 / クレアチンキナーゼ / 抗腫瘍効果 / 悪液質 / 肉腫 / クレアチン / リン酸化クレアチン / クレアチン・キナーゼ

Outline of Research at the Start

本研究では、「エネルギー代謝に重要な役割を果たすクレアチン・サイクルが、担がん体ではがん細胞におけるクレアチン・サイクルの亢進の影響を受けて骨格筋においては障害されており悪液質を惹起している」との仮説を証明し、クレアチン・サイクルを標的化することにより悪液質・がん性サルコペニアの予防・治療に結びつける。

Outline of Final Research Achievements

The creatine cycle is a pathway in which ATP produced in mitochondria is transferred to the cytoplasm in the form of phosphocreatine by mtCK in mitochondria and CKB in the cytoplasm. Then the creatine cycle is regarded as a third energy metabolism pathway. Inhibition of CKs with DNFB in colon cancer cells reduced tumor growth and stemness, and further inhibited the phosphorylation signaling pathways. In skeletal muscle cells, mtCK and CKB are involved in phosphorylation of p38, which activates skeletal muscle differentiation signaling. Induction of CKB expression restored cachexia-induced skeletal muscle maturation defects.

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、クレアチン・サイクルが骨格筋分化と成熟に重要な役割を果たしていることが明らかになった。癌においてはクレアチン・サイクルの抑制は癌を抑制するが、骨格筋においても筋成熟度の低下を招く。しかし、クレアチン・サイクルの活性化は悪液質による骨格筋障害を改善する。これらの結果から、クレアチン・サイクルの骨格筋選択的な活性化により、がん性サルコペニアの改善をもたらすことが可能であり、重要な分子標的と考えられた。

Research Products

• [Int'l Joint Research] 南通大学(中国)
• [Int'l Joint Research] 南通大学(中国)
• [Int'l Joint Research] Nantong University(中国)
• [Journal Article] Nutritional intervention for cancer sarcopenia. (2021)
  • Author(s): Mori T, Kido A, Kawahara I, Nukaga S, Miyagawa Y, Goto K, Mori S, Kishi S, Fujii K, Fujiwara-Tani R, Kuniyasu H
  • Journal Title: Ann Muscloskeletal Med Volume: 5 Issue: 1 Pages: 001-004
  • DOI: 10.17352/amm.000024
  • Peer Reviewed / Open Access
• [Journal Article] Role of Glycated High Mobility Group Box-1 in Gastric Cancer (2021)
  • Author(s): Kishi Shingo、Nishiguchi Yukiko、Honoki Kanya、Mori Shiori、Fujiwara-Tani Rina、Sasaki Takamitsu、Fujii Kiyomu、Kawahara Isao、Goto Kei、Nakashima Chie、Kido Akira、Tanaka Yasuhito、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 10 Pages: 5185-5185
  • DOI: 10.3390/ijms22105185
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancement of Anti-Tumoral Immunity by β-Casomorphin-7 Inhibits Cancer Development and Metastasis of Colorectal Cancer (2021)
  • Author(s): Mori Shiori、Fujiwara-Tani Rina、Kishi Shingo、Sasaki Takamitsu、Ohmori Hitoshi、Goto Kei、Nakashima Chie、Nishiguchi Yukiko、Kawahara Isao、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 15 Pages: 8232-8232
  • DOI: 10.3390/ijms22158232
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of Vitamin B2 and Vitamin E on Cancer-Related Sarcopenia in a Mouse Cachexia Model (2021)
  • Author(s): Mori Takuya、Goto Kei、Kawahara Isao、Nukaga Shota、Wakatsuki Yuma、Mori Shiori、Fujiwara-Tani Rina、Kishi Shingo、Sasaki Takamitsu、Ohmori Hitoshi、Kido Akira、Honoki Kanya、Tanaka Yasuhito、Kuniyasu Hiroki
  • Journal Title: BioMed Volume: 1 Issue: 1 Pages: 50-62
  • DOI: 10.3390/biomed1010004
  • Peer Reviewed / Open Access
• [Journal Article] Linoleic Acid Upregulates Microrna-494 to Induce Quiescence in Colorectal Cancer (2021)
  • Author(s): Ogata Ruiko、Mori Shiori、Kishi Shingo、Sasaki Rika、Iwata Naoya、Ohmori Hitoshi、Sasaki Takamitsu、Nishiguchi Yukiko、Nakashima Chie、Goto Kei、Kawahara Isao、Fujiwara-Tani Rina、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 1 Pages: 225-225
  • DOI: 10.3390/ijms23010225
  • Peer Reviewed / Open Access
• [Journal Article] Targeting claudin‐4 enhances chemosensitivity in breast cancer (2020)
  • Author(s): Luo Yi、Kishi Shingo、Sasaki Takamitsu、Ohmori Hitoshi、Fujiwara‐Tani Rina、Mori Shiori、Goto Kei、Nishiguchi Yukiko、Mori Takuya、Kawahara Isao、Kondoh Masuo、Kuniyasu Hiroki
  • Journal Title: Cancer Science Volume: 111 Issue: 5 Pages: 1840-1850
  • DOI: 10.1111/cas.14361
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of cancer-derived myocardial impairments using a mouse model (2020)
  • Author(s): Miyagawa Yoshihiro、Nukaga Shota、Mori Takuya、Fujiwara-Tani Rina、Fujii Kiyomu、Mori Shiori、Goto Kei、Kishi Shingo、Sasaki Takamitsu、Nakashima Chie、Ohmori Hitoshi、Kawahara Isao、Luo Yi、Kuniyasu Hiroki
  • Journal Title: Oncotarget Volume: 11 Issue: 41 Pages: 3712-3722
  • DOI: 10.18632/oncotarget.27759
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of Nuclear Claudin-4 in Renal Cell Carcinoma (2020)
  • Author(s): Owari Takuya、Sasaki Takamitsu、Fujii Kiyomu、Fujiwara-Tani Rina、Kishi Shingo、Mori Shiori、Mori Takuya、Goto Kei、Kawahara Isao、Nakai Yasushi、Miyake Makito、Luo Yi、Tanaka Nobumichi、Kondoh Masuo、Fujimoto Kiyohide、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 21 Pages: 8340-8340
  • DOI: 10.3390/ijms21218340
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Malic enzyme 1 is associated with tumor budding in oral squamous cell carcinomas. (2020)
  • Author(s): Nakashima C, Kirita T, Yamamoto K, Mori S, Luo Y, Sasaki T, Fujii K, Ohmori H, Kawahara I, Mori T, Goto K, Kishi S, Fujiwara-Tani R, Kuniyasu H
  • Journal Title: Int J Mol Sci Volume: 21 Issue: 19 Pages: 7149-7149
  • DOI: 10.3390/ijms21197149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined administration of lauric acid and glucose improved cancer‐derived cardiac atrophy in a mouse cachexia model (2020)
  • Author(s): Nukaga Shota、Mori Takuya、Miyagawa Yoshihiro、Fujiwara‐Tani Rina、Sasaki Takamitsu、Fujii Kiyomu、Mori Shiori、Goto Kei、Kishi Shingo、Nakashima Chie、Ohmori Hitoshi、Kawahara Isao、Luo Yi、Kuniyasu Hiroki
  • Journal Title: Cancer Science Volume: 111 Issue: 12 Pages: 4605-4615
  • DOI: 10.1111/cas.14656
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Magnetic Hyperthermia Using Self-Controlled Heating Elements Consisting of Fe-Al Milling Alloy Induces Cancer Cell Apoptosis while Preserving Skeletal Muscle (2019)
  • Author(s): Kawahara Isao、Goto Kei、Kodama Kenji、Luo Yi、Fujiwara-Tani Rina、Mori Takuya、Miyagawa Yoshihiro、Tanaka Hirokazu、Kodama Hiroyuki、Hosoito Nobuyoshi、Taniguchi Yukinori、Kuniyasu Hiroki
  • Journal Title: Pathobiology Volume: 86 Issue: 5-6 Pages: 254-262
  • DOI: 10.1159/000501524
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Evaluation of Parameters for Cancer-Induced Sarcopenia in Patients Autopsied after Death from Colorectal Cancer (2019)
  • Author(s): Ohmori Hitoshi、Kawahara Isao、Mori Takuya、Nukaga Shota、Luo Yi、Kishi Shingo、Fujiwara-Tani Rina?、Mori Shiori、Goto Kei、Sasaki Takamitsu、Kuniyasu Hiroki
  • Journal Title: Pathobiology Volume: 86 Issue: 5-6 Pages: 306-314
  • DOI: 10.1159/000503037
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeting claudin‐4 enhances chemosensitivity of pancreatic ductal carcinomas (2019)
  • Author(s): Sasaki Takamitsu、Fujiwara‐Tani Rina、Kishi Shingo、Mori Shiori、Luo Yi、Ohmori Hitoshi、Kawahara Isao、Goto Kei、Nishiguchi Yukiko、Mori Takuya、Sho Masayuki、Kondo Masuo、Kuniyasu Hiroki
  • Journal Title: Cancer Medicine Volume: 8 Issue: 15 Pages: 6700-6708
  • DOI: 10.1002/cam4.2547
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Giving combined medium‐chain fatty acids and glucose protects against cancer‐associated skeletal muscle atrophy (2019)
  • Author(s): Mori Takuya、Ohmori Hitoshi、Luo Yi、Mori Shiori、Miyagawa Yoshihiro、Nukaga Shota、Goto Kei、Fujiwara‐Tani Rina、Kishi Shingo、Sasaki Takamitsu、Fujii Kiyomu、Kawahara Isao、Kuniyasu Hiroki
  • Journal Title: Cancer Science Volume: 110 Issue: 10 Pages: 3391-3399
  • DOI: 10.1111/cas.14170
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Concurrent Expression of CD47 and CD44 in Colorectal Cancer Promotes Malignancy (2019)
  • Author(s): Fujiwara-Tani Rina、Sasaki Takamitsu、Ohmori Hitoshi、Luo Yi、Goto Kei、Nishiguchi Yukiko、Mori Shiori、Nakashima Chie、Mori Takuya、Miyagawa Yoshihiro、Kawahara Isao、Fujii Kiyomu、Kishi Shingo、Tatsumoto Naokuni、Kuniyasu Hiroki
  • Journal Title: Pathobiology Volume: 86 Issue: 4 Pages: 182-189
  • DOI: 10.1159/000496027
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Targeting claudin-4 enhances CDDP-chemosensitivity of gastric cancer (2019)
  • Author(s): Nishiguchi Y, Fujiwara-Tani R, Sasaki T, Luo Y, Ohmori H, Kishi S, Mori S, Goto K, Yasui W, Sho M*, Kuniyasu H
  • Journal Title: Oncotarget Volume: 10 Issue: 22 Pages: 2189-2202
  • DOI: 10.18632/oncotarget.26758
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Effects of antioxidant vitamins on cancerous sarcopenia model mice. (2021)
  • Author(s): Kawahara I, Mori T, Nukaga S, Miyagawa Y, Goto K, Wakatsuki Y, Ohmori H, Fujii K, Mori S, Fujiwara-Tani R, Kishi S, Kuniyasu H
  • Organizer: 80th Annual Meeting of Japanese Association for Cancer
• [Presentation] Impairment of myocardial differentiation in cancer-associated cardiac cachexia. (2021)
  • Author(s): Fujiwara-Tani R, Nukaga S, Mori S, Kishi S, Goto K, Kawahara I, Ohmori H, Kuniyasu H
  • Organizer: 80th Annual Meeting of Japanese Association for Cancer
• [Presentation] Effect of nutritional intervention with medium-chain fatty acids and glucose on cancer-derived myocardial atrophy. (2021)
  • Author(s): Nukaga S, Mori T, Kawahara I, Miyagawa Y, Goto K, Fujiwara-Tani R, Kishi S, Mori S, Fujii K, Ohmori H, Kuniyasu H
  • Organizer: 80th Annual Meeting of Japanese Association for Cancer
• [Presentation] Investigating the mechanism of the anti-tumor effect of medium chain fatty acids. (2021)
  • Author(s): Mori S, Kishi S, Mori T, Fujiwara-Tani R, Goto K, Kawahara I, Nukaga S, Nakashima C, Ohmori H, Kuniyasu H
  • Organizer: 80th Annual Meeting of Japanese Association for Cancer
• [Presentation] Mitochondrial impairment is involved in cancer skeletal muscle atrophy. (2021)
  • Author(s): Mori T, Ohmori H, Kawahara I, Nukaga S, Goto K, Mori S, Kishi S, Fujiwara-Tani R, Luo Y, Kuniyasu H
  • Organizer: 80th Annual Meeting of Japanese Association for Cancer
• [Presentation] 糖質と中鎖脂肪酸の併用経口投与は悪液質における癌関連骨格筋萎縮を抑制する (2020)
  • Author(s): 森 拓也、 大森 斉、川原 勲、宮川良博、後藤 桂、額賀翔太、森 汐莉、岸 真五、谷 里奈、國安弘基
  • Organizer: 第109回日本病理学会総会
• [Presentation] がん悪液質における心筋ミトコンドリア機能障害に対する中鎖脂肪酸の影響 (2020)
  • Author(s): 額賀翔太、大森 斉、森 拓也、宮川良博、後藤 桂、川原 勲、谷 里奈、岸 真吾、森 汐莉、國安弘基
  • Organizer: 第109回日本病理学会総会
• [Presentation] Effects of medium-chain fatty acids on cancer-derived myocardial atrophy (2020)
  • Author(s): Nukaga S, Mori T, Luo Y, Kawahara I, Miyagawa Y, Goto K, Fujiwara-Tani R, Kishi S, Mori S, Ohmori H, Kuniyasu H
  • Organizer: 79th Annual Meeting of Japanese Association for Cancer
• [Presentation] Parameters for cancer-induced sarcopenia in patients autopsied after death from colorectal cancer (2020)
  • Author(s): Mori T, Ohmori H, Luo Y, Kawahara I, Nukaga S, Miyagawa Y, Goto K, Kuniyasu H
  • Organizer: 79th Annual Meeting of Japanese Association for Cancer
• [Presentation] Effect of lauric acid intake on skeletal muscle atrophy caused by 5-FU treatment in CT26 colon cancer mouse model. (2020)
  • Author(s): Kawahara I, Mori T, Luo Y, Nukaga S, Miyagawa Y, Goto K, Ohmori H, Kuniyasu H
  • Organizer: 79th Annual Meeting of Japanese Association for Cancer
• [Presentation] がん悪液質は心筋細胞内の酸化ストレスの蓄積、オートファジーを亢進し、細胞の萎縮を誘導する (2019)
  • Author(s): 宮川良博，森 拓也，後藤 桂，川原 勲，藤井 澄、大森 斉、國安弘基
  • Organizer: 第108回日本病理学会総会
• [Presentation] 中鎖脂肪酸が骨格筋組織と骨格筋細胞代謝に及ぼす影響 (2019)
  • Author(s): 森 拓也、宮川良博、川原 勲、後藤 桂、森 汐莉、岸 真五、谷 里奈、國安弘基
  • Organizer: 第108回日本病理学会総会
• [Presentation] がん悪液質における骨格筋萎縮は腫瘍成長に伴い放出されるHMGB1の影響を受ける (2019)
  • Author(s): 森 拓也、大森 斉、川原 勲、宮川良博、額賀翔太、後藤 桂、羅 奕、國安弘基
  • Organizer: 第4回日本がんサポーティブケア学会学術集会
• [Presentation] がん悪液質における心筋ミトコンドリア機能障害に対する中鎖脂肪酸の効果 (2019)
  • Author(s): 額賀翔太、大森 斉、森 拓也、宮川良博、後藤 桂、川原 勲、國安弘基
  • Organizer: 第4回日本がんサポーティブケア学会学術集会
• [Presentation] Cancer cachexia induces myocardial atrophy by mitochondrial dysfunction producing oxidative stress (2019)
  • Author(s): Miyagawa Y, Ohmori H, Mori T, Nukaga S, Kawahara I, Goto K, Mori S, Kishi S, Kuniyasu H
  • Organizer: 78th Annual Meeting of Japanese Association for Cancer
• [Presentation] Effects of nutritional intervention on cancer-related skeletal muscle atrophy (2019)
  • Author(s): Kawahara I, Ohmori H, Mori T, Miyagawa Y, Nukaga S, Goto K, Mori S, Kishi S, Fujiwara-Tani R, Kuniyasu H
  • Organizer: 78th Annual Meeting of Japanese Association for Cancer
• [Presentation] Role of HMGB1 in skeletal muscle atrophy from cancer cachexia (2019)
  • Author(s): Mori T, Ohmori H, Kawahara I, Miyagawa Y, Nukaga S, Goto K, Mori S, Kishi S, Fujiwara-Tani R, Kuniyasu H
  • Organizer: 78th Annual Meeting of Japanese Association for Cancer
• [Remarks] 奈良県立医科大学分子病理学
  • URL: http://www.naramed-u.ac.jp/~molepath/