Developments of novel treatments based on inhibiting glycolysis with PPARG agonist

• Project/Area Number: 16K19942
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: SAWAYAMA Hiroshi 熊本大学, 医学部附属病院, 医員 (40594875)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: PPAR / GLUT1 / GLUT1阻害剤 / CDK6 / 抗癌剤感受性 / 細胞周期 / Warburg effect / 癌代謝 / PPARG / PKM2 / LDHA / シスプラチン / Glycolysis / PPARγアゴニスト / 癌糖代謝

Outline of Final Research Achievements

Peroxisome proliferator-activated receptor-gamma (PPARγ) is a tumor suppresser gene. Glucose transporter type 1 (Glut1) plays a crucial role in cancer specific metabolism to adapt to the rapid growth and tumor microenvironment. The proliferation of the esophageal squamous cell carcinoma (ESCC) cell lines were inhibited (20-70%) using small interfering (si) iRNA for GLUT1. CDK6 mRNA level significantly reduced and p27 kip mRNA level significantly increased after si-RNA for GLUT1. The anti-proliferative effect of low dose cisplatin was not detected in TE11 after control si-RNA, however low dose cisplatin exerted anti-proliferative effect after si-RNA for GLUT1. PKM2 and LDHA mRNA levels which are associated with glycolysis significantly decreased and PPARγ mRNA levels increased. The new GLUT1 inhibitor exerted a strong antitumor effect with low concentration and an additive effect with combined with cisplatin.

Research Products

• [Journal Article] Total iron-binding capacity is a novel prognostic marker after curative gastrectomy for gastric cancer. (2018)
  • Author(s): Sawayama H, Iwatsuki M, Kuroda D, Toihata T, Uchihara T, Koga Y, Yagi T, Kiyozumi Y, Eto T, Hiyoshi Y, Ishimoto T, Baba Y, Miyamoto Y, Yoshida N, Baba H
  • Journal Title: Int J Clin Oncol. Volume: Apr 9 Issue: 4 Pages: 671-680
  • DOI: 10.1007/s10147-018-1274-7
  • Peer Reviewed
• [Journal Article] Microenvironment in the pathogenesis of gastric cancer metastasis. (2018)
  • Author(s): Sawayama H, Ishimoto T, Baba H.
  • Journal Title: J Cancer Metastasis Treat Volume: 4 Issue: 2 Pages: 10-10
  • DOI: 10.20517/2394-4722.2017.79
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic Factors of Salvage Esophagectomy for Residual or Recurrent Esophageal Squamous Cell Carcinoma After Definitive Chemoradiotherapy. (2018)
  • Author(s): Kiyozumi Y, Yoshida N, Ishimoto T, Yagi T, Koga Y, Uchihara T, Sawayama H, Hiyoshi Y, Iwatsuki M, Baba Y, Miyamoto Y, Watanabe M, Matsuyama T, Oya N, Baba H.
  • Journal Title: World J Surg. Volume: Feb 8. Issue: 9 Pages: 2887-2893
  • DOI: 10.1007/s00268-018-4536-7
  • Peer Reviewed
• [Journal Article] Long Interspersed Element-1 Methylation Level as a Prognostic Biomarker in Gastrointestinal Cancers. (2018)
  • Author(s): Baba Y, Yagi T, Sawayama H, Hiyoshi Y, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, Baba H.
  • Journal Title: Digestion. Volume: 97(1) Issue: 1 Pages: 26-30
  • DOI: 10.1159/000484104
  • Peer Reviewed
• [Journal Article] Controlling Nutritional Status (CONUT) score is a prognostic marker for gastric cancer patients after curative resection. Gastric Cancer. (2018)
  • Author(s): Kuroda D, Sawayama H, Kurashige J, Iwatsuki M, Eto T, Tokunaga R, Kitano Y, Yamamura K, Ouchi M, Nakamura K, Baba Y, Sakamoto Y, Yamashita Y, Yoshida N, Chikamoto A, Baba H
  • Journal Title: Gastric Cancer. Volume: 21(2) Issue: 2 Pages: 204-212
  • DOI: 10.1007/s10120-017-0744-3
  • Peer Reviewed
• [Journal Article] Risk factors for pulmonary morbidities after minimally invasive esophagectomy for esophageal cancer. (2017)
  • Author(s): Uchihara T, Yoshida N, Baba Y, Yagi T, Toihata T, Oda E, Kuroda D, Eto T, Ohuchi M, Nakamura K, Sawayama H, Kinoshita K, Iwatsuki M, Ishimoto T, Sakamoto Y, Baba H.
  • Journal Title: Surg Endosc. Volume: Dec 22 Issue: 6 Pages: 2852-2858
  • DOI: 10.1007/s00464-017-5993-z
  • Peer Reviewed
• [Journal Article] The role of intestinal bacteria in the development and progression of gastrointestinal tract neoplasms. (2017)
  • Author(s): Mima K, Ogino S, Nakagawa S, Sawayama H, Kinoshita K, Krashima R, Ishimoto T, Imai K, Iwatsuki M, Hashimoto D, Baba Y, Sakamoto Y, Yamashita YI, Yoshida N, Chikamoto A, Ishiko T, Baba H
  • Journal Title: Surg Oncol Volume: 26(4) Issue: 4 Pages: 368-376
  • DOI: 10.1016/j.suronc.2017.07.011
  • Peer Reviewed / Open Access
• [Journal Article] Primary colonic well-differentiated / dedifferentiated liposarcoma of the ascending colon: a case report. (2017)
  • Author(s): Sawayama H, Yoshida N, Miyamoto Y, Uchihara T, Toihata T, Yagi T, Hiyoshi Y, Iwatsuki M, Baba Y, Baba H
  • Journal Title: Surg Case Rep. Volume: 3(1) Issue: 1 Pages: 96-96
  • DOI: 10.1186/s40792-017-0373-4
  • Peer Reviewed / Open Access
• [Journal Article] A fascia lata free flap in pelvic exenteration for Fournier gangrene due to advanced rectal cancer: a case report. (2017)
  • Author(s): Sawayama H, Miyanari N, Sugihara H, Iwagami S, Mizumoto T, Kubota T, Haga Y, Baba H.
  • Journal Title: Surg Case Rep. Volume: 3(1) Pages: 74-74
  • Peer Reviewed / Open Access
• [Journal Article] The microbiome and hepatobiliary-pancreatic cancers. (2017)
  • Author(s): Mima K, Nakagawa S, Sawayama H, Ishimoto T, Imai K, Iwatsuki M, Hashimoto D, Baba Y, Yamashita YI, Yoshida N, Chikamoto A, Baba H
  • Journal Title: Cancer Lett. Volume: 402 Pages: 9-15
  • DOI: 10.1016/j.canlet.2017.05.001
  • Peer Reviewed / Open Access
• [Journal Article] Preoperative controlling nutritional status (CONUT) is useful to estimate the prognosis after esophagectomy for esophageal cancer. (2017)
  • Author(s): Yoshida N, Harada K, Baba Y, Kosumi K, Iwatsuki M, Kinoshita K, Nakamura K, Sakamoto Y, Miyamoto Y, Karashima R, Mima K, Sawayama H, Ohuchi M, Chikamoto A, Imamura Y, Watanabe M, Baba H
  • Journal Title: Langenbeck Archiv Surg Volume: 402(2) Issue: 2 Pages: 333-41
  • DOI: 10.1007/s00423-017-1553-1
  • Peer Reviewed
• [Journal Article] Incidence and risk factors of synchronous colorectal cancer in patients with esophageal cancer: an analysis of 480 consecutive colonoscopies before surgery (2016)
  • Author(s): Yoshida N, Tamaoki Y, Baba Y, Sakamoto Y, Miyamoto Y, Iwatsuki M, Shono T, Miyamoto H, Imuta M, Kurashige J, Sawayama H, Tokunaga R, Watanabe M, Sasaki Y, Yamashita Y, Baba H.
  • Journal Title: Int J Clin Oncol Volume: 6 Issue: 6 Pages: 1079-1084
  • DOI: 10.1007/s10147-016-1015-8
  • Peer Reviewed
• [Journal Article] Human Microbiome Fusobacterium Nucleatum in Esophageal Cancer Tissue Is Associated with Prognosis (2016)
  • Author(s): Yamamura K, Baba Y, Nakagawa S, Mima K, Miyake K, Nakamura K, Sawayama H, Kinoshita K, Ishimoto T, Iwatsuki M, Sakamoto Y, Yamashita Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: Clin Cancer Res Volume: 22(22) Issue: 22 Pages: 5574-5581
  • DOI: 10.1158/1078-0432.ccr-16-1786
  • Peer Reviewed
• [Journal Article] Surgical management of partial dentures in the cervicothoracic esophagus. (2016)
  • Author(s): Sawayama H, Miyanari N, Morita K, Matsumoto K, Mizumoto T, Kubota T, Haga Y, Baba H
  • Journal Title: Esophagus Volume: 13(3) Issue: 3 Pages: 270-275
  • DOI: 10.1007/s10388-016-0524-x
  • NAID: 40020882804
  • Peer Reviewed
• [Journal Article] CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer. (2016)
  • Author(s): Izumi D, Ishimoto T, Miyake K, Sugihara H, Eto K, Sawayama H, Yasuda T, Kiyozumi Y, Kaida T, Kurashige J, Imamura Y, Hiyoshi Y, Iwatsuki M, Iwagami S, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Takamori H, Araki N, Tan P, Baba H.
  • Journal Title: Int J Cancer Volume: 1;138(5) Issue: 5 Pages: 1207-19
  • DOI: 10.1002/ijc.29864
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] StageIV大腸癌における原発巣切除症例における原発巣部位に関する検討 (2018)
  • Author(s): 澤山 浩, 宮本 裕士, 日吉 幸晴, 黒田 大介, 大徳 暢哉, 岩槻 政晃, 馬場 祥史, 吉田 直矢, 馬場 秀夫
  • Organizer: 第118回日本外科学会総会
• [Presentation] 食道扁平上皮癌におけるGlut1発現抑制による抗腫瘍効果・機序および抗癌剤感受性変化に関する検討 (2018)
  • Author(s): 澤山 浩, 石本 崇胤, 吉田 直矢, 黒田 大介, 江藤 二男, 八木 泰祐, 内原 智幸, 日吉 幸晴, 岩槻 政晃, 馬場 祥史, 宮本 裕士, 馬場 秀夫
  • Organizer: 第51回制癌剤適応研究会
• [Presentation] S状結腸癌、直腸癌に対する腹腔鏡下手術における腹腔内脂肪量と手術時間に関する検討 (2017)
  • Author(s): 澤山 浩, 宮本 裕士, 日吉 幸晴, 内原 智幸, 清住 雄希, 江藤 二男, 山下 晃平, 大徳 暢哉, 岡留 一雄, 馬場 祥史, 吉田 直矢, 馬場 秀夫
  • Organizer: 第30回日本内視鏡外科学会
• [Presentation] Inhibiting GLUT1 expression suppresses proliferation and enhances anticancer agent sensitivity in esophageal cancer (2017)
  • Author(s): Hiroshi Sawayama, Ishimoto Takatsugu, Naoya Yoshida, Daisuke Kuroda, Tsugio Etho, Yuki Kiyozumi, Taisuke Yagi, Tomoyuki Uchihara, Yukiharu Hiyoshi, Masaaki Iwatsuki, Yoshifumi Baba, Yuji Miyamoto, Hideo Baba
  • Organizer: 第28回消化器癌発生学会
• [Presentation] 胃癌に対する根治切除術症例における術前の血清鉄の測定意義 (2017)
  • Author(s): 澤山 浩, 岩槻 政晃, 吉田 直矢, 馬場 祥史, 坂本 快郎, 宮本 裕士, 木下 浩一, 問端 輔, 内原 智幸, 馬場 秀夫
  • Organizer: 第25回JDDW 2017
• [Presentation] 結腸右半切除術における主リンパ節郭清術式 (2017)
  • Author(s): 澤山 浩, 宮本 裕士, 日吉 幸晴, 黒田 大介, 大徳 暢哉, 江藤 二男, 清住 雄希, 八木 泰祐, 内原 智幸, 岩槻 政晃, 馬場 祥史, 吉田 直矢, 馬場 秀夫
  • Organizer: 第42回日本大腸肛門病学会
• [Presentation] Surgical strategy for the adenocarcinoma of gastroesophageal junction (2017)
  • Author(s): Hiroshi Sawayama, Masaaki Iwatsuki, Naoya Yoshida, Yoshifumi Baba, Yuji Miyamoto, Tasuku Toihata, Tomoyuki Uchihara and Hideo Baba
  • Organizer: 第71回日本消化器外科学会
• [Presentation] リンパ節転移範囲・郭清効果に基づいた胃上部胃癌に対する術式の検討 (2017)
  • Author(s): 澤山 浩, 岩槻 政晃, 吉田 直矢, 馬場 祥史, 坂本 快郎, 宮本 裕士, 木下 浩一, 問端 輔, 内原 智幸, 馬場 秀夫
  • Organizer: 第71回手術手技研究会
• [Presentation] Glucose transporter 1 is associated with proliferation and prognosis on esophageal squamous cell carcinoma (2017)
  • Author(s): Hiroshi Sawayama, Takatsugu Ishimoto, Masayuki Watanabe, Naoya Yoshida, Yoshifumi Baba, Hidetaka Sugihara, Daisuke Izumi, Junji Kurashige, Hideo Baba
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] 腹腔内腫瘤に対する腹腔鏡下腫瘍生検に関する検討 (2016)
  • Author(s): 澤山浩、宮成信友、中尾陽佑、杉原栄孝、岩上志朗、水元孝郎、久保田竜生、芳賀克夫、片渕茂、馬場秀夫
  • Organizer: 第71回日本消化器外科学会総会
  • Place of Presentation: アスティとくしま（徳島県）
• [Presentation] Gastrectomy for gastric cancer with synchronous multiple primary cancers. (2016)
  • Author(s): Sawayama H、Iwatsuki M, Yoshida N, Baba Y, Sakamoto Y, Miyamoto Y, Kinoshita K, Tokunaga R, Toihata T, Uchihara T, Baba H
  • Organizer: IASGO 2016
  • Place of Presentation: ソウル・韓国
  • Int'l Joint Research
• [Presentation] Lymph node metastasis ratio and serum CA19-9 level were associated with early recurrence after gastrectomy for gastric cancer (2016)
  • Author(s): Sawayama H、Iwatsuki M, Yoshida N, Baba Y, Sakamoto Y, Miyamoto Y, Kinoshita K, Tokunaga R, Toihata T, Uchihara T, Baba H
  • Organizer: 4th International Conference of FACO
  • Place of Presentation: 廈門・中国
  • Int'l Joint Research
• [Presentation] 急性胆嚢炎に対する経皮経肝胆嚢ドレナージ後の待機的手術に関する検討 (2016)
  • Author(s): 澤山 浩、宮成信友、中尾陽佑、山尾宣暢、杉原栄孝、岩上志朗、水元孝郎、久保田竜生、芳賀克夫、片渕茂、馬場秀夫
  • Organizer: JDDW2016
  • Place of Presentation: 神戸コンベンションセンター（兵庫県）