Elucidation of the mechanism of acquisition of anticancer drug resistance caused by mitochondrial disorders

• Project/Area Number: 21K20808
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Nara Medical University
• Principal Investigator: Mori Shiori 奈良県立医科大学, 医学部, 助教 (00907032)
• Project Period (FY): 2021-08-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 抗がん剤耐性 / ミトコンドリア / ρ0形質 / 幹細胞性 / ROS / 悪液質 / 薬剤耐性 / ミトコンドリアDNA / 抗癌剤耐性

Outline of Research at the Start

がん治療における抗がん剤耐性は疾患予後を左右する重要な因子であり。これまでの研究においてもその全容は明らかになっておらず、治療上の問題となっている。これに対し、申請者はミトコンドリアDNA部分欠損細胞(部分ρ0細胞)を樹立し、多剤耐性能を獲得したことを明らかにした。本研究では、ρ0細胞、部分ρ0細胞の代謝機能と幹細胞性の変化、および、ミトコンドリアDNA障害の詳細について解析を行い、ミトコンドリア障害に起因する抗がん剤抵抗性の機序を解明することにより、抗がん剤耐性の克服に寄与する。

Outline of Final Research Achievements

Anticancer drug resistance is one of the key barriers in cancer therapy. Recently involvement of mitochondria in anticancer drug resistance has been focused. In this study, we established cancer cells with mitochondrial DNA damage to analyze their characteristics. We found that cancer cells partially damaged in mitochondrial DNA (partial ρ0 cells) showed increased pro-inflammatory effects and induced cachexia, along with decreased proliferative capacity, oxygen consumption and stemness, and increased ROS production. They also showed anticancer drug resistance. Since cancer cells acquired partial ρ0 phenotype upon continuous treatment with anticancer drugs, this is a new mechanism for the acquisition of anticancer drug resistance.

Academic Significance and Societal Importance of the Research Achievements

化学療法によって誘導されるミトコンドリア障害が抗がん剤抵抗性を誘導することが明らかになった。抗がん剤によるミトコンドリアDNAの障害が抗がん剤耐性をもたらすことは、ほとんどの抗がん剤において一般的に生じ得る抗がん剤耐性獲得機序であり、がん治療において重要な知見と見なされる。今後この新たな耐性抑制の標的を抽出し治療戦略に結びつけることが出来れば、がん化学療法における大きな進展となり、癌患者の予後改善をもたらすと期待される。

Research Products

• [Int'l Joint Research] 南通大学(中国)
• [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] BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer (2021)
  • Author(s): Fujiwara-Tani Rina、Okamoto Ayaka、Katsuragawa Hiroyuki、Ohmori Hitoshi、Fujii Kiyomu、Mori Shiori、Kishi Shingo、Sasaki Takamitsu、Nakashima Chie、Kawahara Isao、Hojo Yudai、Nishiguchi Yukiko、Mori Takuya、Mizumoto Takeshi、Nagai Kenta、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 23 Pages: 12724-12724
  • DOI: 10.3390/ijms222312724
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] The regulation of mitochondria metabolism is correlated with gemcitabine resistance in MIA-PaCa-2 cell line. (2021)
  • Author(s): Fujiwara-Tani R, Sasaki T, Mori S, Kishi S, Kuniyasu H
  • Organizer: AACR Annual Meeting 2021
  • Int'l Joint Research
• [Presentation] Dual inhibition of direct metabolic features targets osteosarcoma stem cells. (2021)
  • Author(s): Kishi S, Honoki K, Mori S, Kuniyasu H, Tanaka Y
  • Organizer: Asia Pacific Musculoskeletal Tumor Society 2021
  • Int'l Joint Research
• [Presentation] 腫瘍における持続的抗がん剤処理はpartial ρ0細胞類似形質をもたらし炎症を惹起する (2021)
  • Author(s): 森 汐莉、岸 真五、谷 里奈、大森 斉、藤井 澄、森 拓也、川原 勲、國安弘基
  • Organizer: 第110回日本病理学会総会
• [Presentation] 骨腫瘍におけるSアデノシルメチオニンの抗腫瘍効果の検討 (2021)
  • Author(s): 森 汐莉、岸 真五、朴木寛也、谷 里奈、塚本真治、藤井宏真、城戸 顕、國安弘基、田中康仁
  • Organizer: 第54回日本整形外科学会骨軟部腫瘍学術集会
• [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
• [Remarks] 奈良県立医科大学分子病理学
  • URL: http://www.naramed-u.ac.jp/~molepath/