Elucidation of the mechanism of mitochondorial dynamics for chemoresistance and creation of novel therapeutic methods

• Project/Area Number: 20K18699
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Kumamoto University
• Principal Investigator: Kawahara Kenta 熊本大学, 病院, 助教 (90732735)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 口腔癌 / シスプラチン耐性 / ミトコンドリア / カルシウム / オルガネラ / カルシウムキレーター / ストア依存性カルシウムチャネル / 抗癌剤耐性

Outline of Research at the Start

治療抵抗性の口腔癌に対して、Ca2+・ミトコンドリアネットワークの観点からシスプラチン耐性機構を解明するとともに、細胞死誘発Ca2+シグナルを特異的に増強させ、効果的なシスプラチンによる癌治療法の創出を目指す。

Outline of Final Research Achievements

The purpose of this study is to elucidate the drug resistance mechanism involving calcium-mitochondria in oral cancer. To specifically enhance cell death-induced calcium signaling and to obtain an effective antitumor effect of cisplatin, we used an extracellular calcium scavenger: EGTA, an intracellular calcium scavenger: BAPTA-AM, and a mitochondrial calcium uniporter inhibitor: Ru360. The results showed that the combination of cisplatin and EGTA inhibited cell proliferation and cell death against cisplatin-resistant oral cancer cell lines.
Exposure to cisplatin also decreased mitochondrial calcium in the resistant strain, while calcium accumulation was observed in the sensitive strain.

Academic Significance and Societal Importance of the Research Achievements

他癌腫において、カルシウム拮抗薬であるニフェジピンは抗癌剤の組織運搬能を増強させ、ベラパミルは腫瘍の脈管構造を変化させることで放射線感受性を増強させると報告されている。本研究成果で得られた、口腔癌細胞株におけるカルシウム動態の変化が治療抵抗性に影響を与えているならば、既存するカルシウム拮抗薬をドラッグリポジショニングとして使用することで、より治療効果を高める可能性が示唆された。また口腔癌の中でも放射線や化学療法に抵抗性のある稀少癌：唾液腺癌や、他の領域の癌に対する研究の基盤や治療法の発見にもつながる可能性が示唆された。

Research Products

• [Journal Article] Air Plasma-Activated Medium Evokes a Death-Associated Perinuclear Mitochondrial Clustering (2022)
  • Author(s): Manami Suzuki-Karasaki, Takashi Ando, Yushi Ochiai, Kenta Kawahara, Miki Suzuki-Karasaki, Hideki Nakayama, Yoshihiro Suzuki-Karasaki.
  • Journal Title: International Journal of Molecular Science Volume: 23 Issue: 3 Pages: 1124-1124
  • DOI: 10.3390/ijms23031124
  • Peer Reviewed / Open Access
• [Journal Article] Naringenin potentiates anti-tumor immunity against oral cancer by inducing lymph node CD169-positive macrophage activation and cytotoxic T cell infiltration (2022)
  • Author(s): Kawaguchi S、Kawahara a、Fujiwara Y、Ohnishi K、Pan C、Yano H、Hirosue A、Nagata M、Hirayama M、Sakata J、Nakashima H、Arita H、Yamana K、Gohara S、Nagao Y、Maeshiro M、Iwamoto A、Hirayama M、Yoshida R、Komohara Y、Nakayama H
  • Journal Title: Cancer Immunology, Immunotherapy Volume: - Issue: 9 Pages: 2127-2139
  • DOI: 10.1007/s00262-022-03149-w
  • Peer Reviewed / Open Access
• [Journal Article] miR-30a attenuates drug sensitivity to 5-FU by modulating cell proliferation possibly by downregulating cyclin E2 in oral squamous cell carcinoma. (2021)
  • Author(s): Kenta Kawahara, Masashi Nagata, Ryoji Yoshida, Akiyuki Hirosue, Takuya Tanaka, Yuichiro Matsuoka, Hidetaka Arita, Hikaru Nakashima, Junki Sakata, Keisuke Yamana, Sho Kawaguchi, Shunsuke Gohara, Yuka Nagao, Masatoshi Hirayama, Nozomu Takahashi, Mayumi Hirayama, Hideki Nakayama
  • Journal Title: Biochemistry Biophysics Reports Volume: 21 Pages: 28-28
  • DOI: 10.1016/j.bbrep.2021.101114
  • Peer Reviewed / Open Access
• [Presentation] Effect of cisplatin on calcium dynamics in oral cancer (2022)
  • Author(s): 篠原 光佑
  • Organizer: 第81回 日本癌学会学術総会
• [Presentation] CD169の高発現は口腔扁平上皮癌において抗腫瘍免疫を活性化させる (2021)
  • Author(s): 川口 翔
  • Organizer: 第66回 日本口腔外科学会総会・学術大会
• [Presentation] Mitochondrial calcium regulation contributes to CDDP resistance in oral cancer (2020)
  • Author(s): 平山 真弓
  • Organizer: 第79回 日本癌学会学術総会