Effect of AdipoRon on the growth of pancreatic cancer cells in primary culture and obese prediabetic mice.

• Project/Area Number: 16K10594
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Chiba Cancer Center (Research Institute) (2018); Shimane University (2016-2017)
• Principal Investigator: Takenaga Keizo 千葉県がんセンター(研究所), がん遺伝創薬研究室, 特任研究員 (80260256)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: AdipoRon / 膵癌 / 糖尿病 / 肥満 / 腫瘍増殖 / 膵臓がん / 抗糖尿病薬 / アディポネクチン受容体 / アゴニスト / 細胞死 / 前２型糖尿病 / 癌

Outline of Final Research Achievements

Based on the finding that the antidiabetic drug AdipoRon induced cell death of human pancreatic cancer cells and reduced tumor growth in vivo, we examined the effect of AdipoRon on cell death in primary spheroid culture of pancreatic cancer cells isolated from pancreatic cancer patients. We found that AdipoRon induced necrotic cell death of pancreatic cancer cells in successfully established primary spheroid culture. We also examined the effect of AdipoRon on tumor growth of orthotopically implanted mouse pancreatic cancer cells in high-fat diet-induced obese prediabetic mouse model (B6J-DIO). We found that amelioration of obese rather than that of diabetic condition was important for suppression of tumor growth as well as the antitumor effect of AdipoRon.

Academic Significance and Societal Importance of the Research Achievements

アディポネクチン受容体に結合し抗糖尿病作用を示す薬剤として見出されたAdipoRonが膵癌患者由来の初代スフェロイド培養系において殺細胞効果を示すことが確認され、将来の治療に資する可能性がある。また、前糖尿病および肥満が膵癌の増殖、進展に影響するかどうかを、またそれに対してAdipoRon投与がどのような効果を示すかを肥満前糖尿病モデルマウスで検証し、糖尿病症状の軽減そのものよりも肥満の解消の方が膵癌増殖の抑制やAdipoRonの抗腫瘍効果に重要であることを見出した。

Research Products

• [Journal Article] Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis (2018)
  • Author(s): 17.Akimoto M, Maruyama R, Kawabata Y, Tajima Y, Takenaga K.
  • Journal Title: Cell Death & Disease Volume: 9 Issue: 8 Pages: 804-804
  • DOI: 10.1038/s41419-018-0851-z
  • URL: https://localhost/en/publications/5bc250ec-558c-41d5-b982-1e36ed1fbbd8
  • Peer Reviewed / Open Access
• [Journal Article] Role of the IL-33/ST2L axis in colorectal cancer progression (2018)
  • Author(s): Akimoto Miho、Takenaga Keizo
  • Journal Title: Cellular Immunology Volume: - Pages: 103740-103740
  • DOI: 10.1016/j.cellimm.2017.12.014
  • Peer Reviewed / Open Access
• [Journal Article] Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner (2018)
  • Author(s): Sumi Chisato、Okamoto Akihisa、Tanaka Hiromasa、Nishi Kenichiro、Kusunoki Munenori、Shoji Tomohiro、Uba Takeo、Matsuo Yoshiyuki、Adachi Takehiko、Hayashi Jun-Ichi、Takenaga Keizo、Hirota Kiichi
  • Journal Title: PLOS ONE Volume: 13 Issue: 2 Pages: e0192796-e0192796
  • DOI: 10.1371/journal.pone.0192796
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIF-2α dictates the susceptibility of pancreatic cancer cells to TRAIL by regulating survivin expression (2017)
  • Author(s): Harashima Nanae、Takenaga Keizo、Akimoto Miho、Harada Mamoru
  • Journal Title: Oncotarget Volume: 8 Issue: 26 Pages: 42887
  • DOI: 10.18632/oncotarget.17157
  • NAID: 120006532063
  • URL: https://pure.teikyo.jp/en/publications/f52d6fe2-3728-4ca5-8f16-d66f908f3f75
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIF-1-mediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death (2017)
  • Author(s): Okamoto Akihisa、Sumi Chisato、Tanaka Hiromasa、Kusunoki Munenori、Iwai Teppei、Nishi Kenichiro、Matsuo Yoshiyuki、Harada Hiroshi、Takenaga Keizo、Bono Hidemasa、Hirota Kiichi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 3816-3816
  • DOI: 10.1038/s41598-017-03980-7
  • NAID: 120006364104
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cytoplasmic transfer of heritable elements other than mtDNA from SAMP1 mice into mouse tumor cells suppresses their ability to form tumors in C57BL6 mice (2017)
  • Author(s): Shimizu Akinori、Tani Haruna、Takibuchi Gaku、Ishikawa Kaori、Sakurazawa Ryota、Inoue Takafumi、Hashimoto Tetsuo、Nakada Kazuto、Takenaga Keizo、Hayashi Jun-Ichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 493 Issue: 1 Pages: 252-257
  • DOI: 10.1016/j.bbrc.2017.09.035
  • NAID: 120007134703
  • Peer Reviewed / Open Access
• [Journal Article] Association of predicted pathogenic mutations in mitochondrial ND genes with distant metastasis in NSCLC and colon cancer (2017)
  • Author(s): Koshikawa Nobuko、Akimoto Miho、Hayashi Jun-Ichi、Nagase Hiroki、Takenaga Keizo
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 15535-15535
  • DOI: 10.1038/s41598-017-15592-2
  • NAID: 120007134603
  • URL: https://localhost/en/publications/d61b71da-6444-40de-98b9-1a07aef04eca
  • Peer Reviewed / Open Access
• [Journal Article] Soluble IL-33 receptor sST2 inhibits colorectal cancer malignant growth by modifying the tumour microenvironment. (2016)
  • Author(s): Akimoto M, Maruyama R, Takamaru H, Ochiya T, Takenaga K.
  • Journal Title: Nat Commun. Volume: 7 Issue: 1 Pages: 13589-13589
  • DOI: 10.1038/ncomms13589
  • Peer Reviewed / Open Access
• [Journal Article] The antioxidant N-acetyl cysteine suppresses lidocaine-induced intracellular reactive oxygen species production and cell death in neuronal SH-SY5Y cells (2016)
  • Author(s): Okamoto A, Tanaka M, Sumi C, Oku K, Kusunoki M, Nishi K, Matsuo Y, Takenaga K, Shingu K, Hirota K
  • Journal Title: BMC Anesthesiol Volume: 16 Issue: 1 Pages: 104-104
  • DOI: 10.1186/s12871-016-0273-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] AdipoRon induces cell death of pancreatic cancer cells through triggering Ca2+ uptake via mitochondrial Ca2+ uniporter (2017)
  • Author(s): Akimoto M, Takenaga K.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Reevaluation of association of mitochondrial ND gene pathogenic mutations with metastasis in NSCLC and colon cancer (2017)
  • Author(s): Koshikawa N, Akimoto M, Hayashi J, Nagase H, Takenaga K.
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] ヒト癌におけるミトコンドリアND遺伝子変異の病因性予測と遠隔転移との関連性の検討 (2017)
  • Author(s): 越川信子、秋元美穂、林純一、永瀬浩喜、竹永啓三
  • Organizer: 第15回がんとハイポキシア研究会
• [Presentation] 可溶性ST2は炎症性のがん微小環境を修飾し膵がん細胞の皮下増殖を抑制する (2017)
  • Author(s): 秋元美穂、岡崎具樹、竹永啓三
  • Organizer: 第15回がんとハイポキシア研究会
• [Presentation] 可溶性ST2は炎症性のがん微小環境の修飾を介して大腸がんの増殖および転移を抑制する (2016)
  • Author(s): 秋元美穂、丸山理留敬、竹永啓三
  • Organizer: 第14回がんとハイポキシア研究会
  • Place of Presentation: 岐阜グランドホテル（岐阜）
  • Year and Date: 2016-11-04
• [Presentation] 可溶性IL-33受容体sST2は大腸がん同所移植モデルにおいて腫瘍増殖および肝転移を抑制する (2016)
  • Author(s): 秋元美穂、竹永啓三
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-10-08
• [Presentation] S100A4-MetAP2相互作用を阻害する合成ペプチドによる腫瘍血管新生と腫瘍増殖の抑制 (2016)
  • Author(s): 竹永啓三、落谷孝広、遠藤英也
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-10-07
• [Presentation] mtDNA変異が制御する転移の予測因子としての乳酸トランスポーターMCT4の核局在 (2016)
  • Author(s): 越川信子、秋元美穂、植田健、飯笹俊彦、鍋谷圭宏、井内俊彦、永瀬浩喜、竹永啓三
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-10-07
• [Presentation] IL-33はprogrammed oncosis耐性高転移性肺癌細胞をがん微小環境下において選別する (2016)
  • Author(s): 秋元美穂、竹永啓三
  • Organizer: 第25回日本がん転移学会
  • Place of Presentation: 米子コンベンションセンター（米子）
  • Year and Date: 2016-07-21