Role of rho0 phenotype on acquisition of gemcitabine resistance in pancreatic ductal carcinoma

• Project/Area Number: 19K16564
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Nara Medical University
• Principal Investigator: Fujiwara-Tani Rina 奈良県立医科大学, 医学部, 講師 (20783872)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵管癌 / ゲムシタビン / 薬剤耐性 / ミトコンドリアDNA / 部分ρ０形質 / 酸化的リン酸化 / 活性酸素種 / 膵癌 / 低酸素 / ρ0形質 / 酸化ストレス / ミトコンドリアDNA障害 / エネルギー代謝 / ミトコンドリア遺伝子

Outline of Research at the Start

本研究では、①ρ0化によりゲムシタビン耐性が獲得されるか、②ゲムシタビン耐性に関連するρ0化に伴う遺伝子発現や代謝変化は何か、 ③ρ0化に伴う悪性形質亢進の原因は何か、④ρ0化はゲムシタビン以外の薬剤耐性にも関与するのか、⑤ゲムシタビンががん細胞のρ0化を誘導するのか、の5点について解明を行う。膵管癌の臨床において、ゲムシタビン投与中はコントロールされていた病勢が耐性出現とともに他剤投与によっても制御不能になることはしばしば経験されるところであり、この5点を解明することにより、抗がん剤耐性、悪性形質、ρ0化の機序が明らかとなり、ゲムシタビン耐性の獲得予防・耐性解除につながると考えられる。

Outline of Final Research Achievements

The gemcitabine-resistant cell line established by continuous gemcitabine treatment had a partial ρ0 phenotype, indicating a partial deletion in mitochondrial DNA. These cells acquired gemcitabine resistance by suppressing gemcitabine-induced mitochondrial ROS production through reduction of mitochondrial membrane potential and inhibition of oxidative phosphorylation by gemcitabine treatment. Thus, it was suggested that acquisition of the partial ρ0 phenotype due to DNA toxicity of the anticancer drug itself plays an important role in anticancer drug resistance. It is hoped that more effective chemotherapy will be realized by investigating therapies that target this partial ρ0 phenotype.

Academic Significance and Societal Importance of the Research Achievements

癌細胞における抗がん剤耐性の獲得に、抗がん剤の有するミトコンドリアDNAに対する毒性に起因する部分ρ０形質の獲得が重要な役割を果たすことが示された。この結果は、抗癌剤による化学療法そのものが耐性を惹起する内在的危険性を有することを、その機序を明らかにしたものであり、重要な知見と考えられる。今後は部分ρ０形質の獲得の抑制、あるいは、部分ρ０形質を克服する治療法を開発することにより、抗がん剤耐性の獲得を抑制し、より効果的な化学療法を可能にすることが可能になると期待される。

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)
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• [Journal Article] Role of Glycated High Mobility Group Box-1 in Gastric Cancer (2021)
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• [Journal Article] Enhancement of Anti-Tumoral Immunity by β-Casomorphin-7 Inhibits Cancer Development and Metastasis of Colorectal Cancer (2021)
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  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 15 Pages: 8232-8232
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• [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
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• [Journal Article] BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer (2021)
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• [Journal Article] Linoleic Acid Upregulates Microrna-494 to Induce Quiescence in Colorectal Cancer (2021)
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  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 1 Pages: 225-225
  • DOI: 10.3390/ijms23010225
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• [Journal Article] Targeting claudin‐4 enhances chemosensitivity in breast cancer (2020)
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  • Journal Title: Cancer Science Volume: 111 Issue: 5 Pages: 1840-1850
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• [Journal Article] Role of Clostridium perfringens Enterotoxin on YAP Activation in Colonic Sessile Serrated Adenoma/Polyps with Dysplasia (2020)
  • Author(s): Fujiwara-Tani Rina、Fujii Kiyomu、Mori Shiori、Kishi Shingo、Sasaki Takamitsu、Ohmori Hitoshi、Nakashima Chie、Kawahara Isao、Nishiguchi Yukiko、Mori Takuya、Sho Masayuki、Kondoh Masuo、Luo Yi、Kuniyasu Hiroki
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 11 Pages: 3840-3840
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• [Journal Article] Diabetes mellitus is associated with liver metastasis of colorectal cancer through production of biglycan-rich cancer stroma (2020)
  • Author(s): Fujiwara-Tani Rina、Sasaki Takamitsu、Fujii Kiyomu、Luo Yi、Mori Takuya、Kishi Shingo、Mori Shiori、Matsushima-Otsuka Sayako、Nishiguchi Yukiko、Goto Kei、Kawahara Isao、Kondoh Masuo、Sho Masayuki、Kuniyasu Hiroki
  • Journal Title: Oncotarget Volume: 11 Issue: 31 Pages: 2982-2994
  • DOI: 10.18632/oncotarget.27674
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• [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
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• [Journal Article] Anti-stem cell property of pterostilbene in gastrointestinal cancer cells. (2020)
  • Author(s): Mori S, Kishi S, Honoki K, Fujiwara-Tani R, Moriguchi T, Sasaki T, Fujii K, Tsukamoto S, Fujii H, Kido A, Tanaka Y, Luo Y, Kuniyasu H.
  • Journal Title: Int J Mol Sci. Volume: 21 Issue: 24 Pages: 9347-9347
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• [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] Clostridium perfringens enterotoxin induced claudin-4 to activate YAP in oral squamous cell carcinomas. (2020)
  • Author(s): Nakashima C, Yamamoto K, Kishi S, Sasaki T, Ohmori H, Fujiwara-Tani R Mori S, Kawahara I, Nishiguchi Y, Mori T, Kondoh M, Luo Y, Kirita T, Kuniyasu H
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  • DOI: 10.18632/oncotarget.27424
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• [Journal Article] Role of Metastasis-Related Genes in Cisplatin Chemoresistance in Gastric Cancer (2019)
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• [Journal Article] Magnetic Hyperthermia Using Self-Controlled Heating Elements Consisting of Fe-Al Milling Alloy Induces Cancer Cell Apoptosis while Preserving Skeletal Muscle (2019)
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  • Journal Title: Pathobiology Volume: 86 Issue: 5-6 Pages: 254-262
  • DOI: 10.1159/000501524
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• [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
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• [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
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• [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] がん性心臓悪液質におけるミトコンドリア変化の検討 (2021)
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  • Organizer: 第110回日本病理学会総会
• [Presentation] 低酸素が膵癌の化学療法抵抗性獲得に与える影響 (2021)
  • Author(s): 高木忠隆、谷 里奈、森 汐莉、赤堀宇広、中川顕志、長井美奈子、岸 真五、寺井太一、庄 雅之、國安弘基
  • Organizer: 第110回日本病理学会総会
• [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] New therapeutic strategy targeting hypoxia-induced mitochondrial dysfunction and stemness in pancreatic cancer. (2021)
  • Author(s): Takagi T, Fujiwara-Tani R, Mori S, Akahori T, Nishiwada S, Nakagawa K, Nagai M, Kishi S, Terai T, Sho M, Kuniyasu H
  • Organizer: 80th Annual Meeting of Japanese Association for Cancer
• [Presentation] ρ0細胞の復帰変異株における悪性形質の検討 (2020)
  • Author(s): 森 汐莉、谷 里奈、岸 真吾、國安弘基
  • Organizer: 第109回日本病理学会総会
• [Presentation] クレアチン・キナーゼの大腸癌細胞における役割 (2020)
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  • Organizer: 第109回日本病理学会総会
• [Presentation] Mitochondria metabolism is correlated with gemcitabine resistance in MIA-PaCa-2. (2020)
  • Author(s): Fujiwara-Tani R, Sasaki T, Mori S, Kishi S, Kuniyasu H
  • Organizer: 79th Annual Meeting of Japanese Association for Cancer
• [Presentation] Alteration of ρ0 cells in in vivo environment (2020)
  • Author(s): Mori S, Fujiwara-Tani R, Kishi S, Kuniyasu H
  • Organizer: 79th Annual Meeting of Japanese Association for Cancer
• [Presentation] The creatine kinase is a metabolic vulnerability in Osteosarcoma. (2020)
  • Author(s): Kishi S, Mori S, Fujiwara-Tani R, Hojo Y, Owar T, Mori T, Nukaga S, Kita M, Sasaki R, Honoki K, Kuniyasu H
  • Organizer: 79th Annual Meeting of Japanese Association for Cancer
• [Presentation] 膵管癌細胞株MIA-PaCa-2のgemcitabine耐性獲得におけるミトコンドリア代謝変化の検討 (2019)
  • Author(s): 谷 里奈、森 汐莉、佐々木隆光、岸 真五、國安弘基
  • Organizer: 第108回日本病理学会総会
• [Presentation] 間葉系幹細胞からのオルガネラの移動は癌細胞の抗がん剤耐性に寄与する (2019)
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  • Organizer: 第108回日本病理学会総会
• [Presentation] Linoleic acid-related signal pathway associated with dormant stemness (2019)
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• [Presentation] ER-mitochondria tethering by PDZD8 regulates mitochondrial ATP-ROS balance in osteosarcoma cells (2019)
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  • Organizer: 78th Annual Meeting of Japanese Association for Cancer
• [Presentation] Involvement of energy metabolism and malignant phenotype in cancer cells (2019)
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  • 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/