Elucidation of glutamine metabolism in tumor endothelial cells to develop novel anti-cancer drugs

2020 Fiscal Year Annual Research Report

• Project/Area Number: 19K19220
• Research Institution: Hokkaido University
• Principal Investigator: ANNAN DORCAS・AKUBAMUHYIA 北海道大学, 歯学研究院, 学術研究員 (30837240)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: Slc7a11 / glutamate / tumor endothelial cell / sulfasalazine / oxidative stress / bioenergetics

Outline of Annual Research Achievements

TECs and NECs normal endothelial cells were successfully isolated. The metabolomes in each cell type were analyzed by CE-MS metabolomics. Both unlabeled and carbon-13 labeled glutamine were used together with unlabelled glucose as major substrates. The metabolites within the cells (intracellular) and metabolites released into the culture media (extracellular) were analyzed. NECs converted glutamine primarily to GABA, whereas tumor endothelial cells produced more glutamate, asparagine, and aspartate from glutamine. In this year, I have obtained the results as described below.
1.Normal endothelial cells and tumor endothelial cells have different metabolic endpoints for glutamine - NECs produce lots of GABA, whereas TECs produce more metabolic intermediates such as glutamate, asparagine. 2.Glycolysis (extracellular acidification) is higher in TECs produce than in NECs, while oxygen consumption and spare respiratory capacity are decreased in the TECs compared to the NECs.
3.Inhibition of the glutamate-cysteine antiporter Slc7a11 with the drug sulfasalazine leads to a significant decrease in TEC proliferation compared to NECs.
4.TECs are more dependent on a functional antioxidant system to continue proliferation; therefore, in the presence of cystine or cysteine, the adverse effects of sulfasalazine were abrogated.
5.Sulfasalazine treatment decreased tumor weight and tumor angiogenesis in tumor-bearing mice. 6.Changes in the extracellular matrix and tumor microenvironment were not significantly different between the treated tumor-bearing mice and their controls.

Research Products

• [Journal Article] Correlation between endothelial CXCR7 expression and clinicopathological factors in oral squamous cell carcinoma (2021)
  • Author(s): 2.Yanagiya M, Dawood RIH, Maishi N, Hida Y, Torii C, Annan DA, Kikuchi H, Yanagawa Matsuda A, Kitamura T, Tei K, Shindoh M, Tanaka S, Kitagawa Y, Hida K
  • Journal Title: Pathology International Volume: - Pages: 1-9
  • DOI: 10.1111/pin.13094
  • Peer Reviewed
• [Journal Article] Inhibition of stromal biglycan promotes normalization of the tumor microenvironment and enhances chemotherapeutic efficacy (2021)
  • Author(s): Li C, Maishi N, Annan DA, Young MF, Morimoto H, Morimoto M, Nam JM, Hida Y, Hida K
  • Journal Title: Breast Cancer Res Volume: - Pages: -
  • DOI: 10.21203/rs.3.rs-142861/v1
  • Peer Reviewed
• [Journal Article] がん治療標的としての腫瘍血管内皮細胞の特異性 (2020)
  • Author(s): 間石奈湖, Annan DA, 樋田京子
  • Journal Title: 炎症と免疫 Volume: 28 Pages: 35-40
• [Journal Article] Tumor Endothelial Cell - A Biological Tool for Translational Cancer Research (2020)
  • Author(s): Annan DA, Kikuchi H, Maishi N, Hida Y and Hida K
  • Journal Title: Int. J. Mol Sci Volume: 21 Pages: 3238
  • DOI: 10.3390/ijms21093238
  • Peer Reviewed / Open Access
• [Journal Article] Chemotherapy-induced IL-8 upregulates MDR1/ABCB1 in tumor blood vessels and results in unfavorable outcome (2020)
  • Author(s): Kikuchi H、Maishi N、Annan DA.、Mohammad TA、Dawood R、Sato M、Morimoto M、Takeda R、Ishizuka K、Matsumoto R、Akino T、Tsuchiya K、Abe T、Osawa T、Miyajima N、Maruyama S、Harabayashi T、 Azuma M、Yamashiro K、Ameda K、Kashiwagi A、Matsuno Y、Hida Y、Shinohara N、Hida K
  • Journal Title: Cancer Research Volume: 80(14) Pages: 2996-3008
  • DOI: 10.1158/0008-5472.CAN-19-3791
  • Peer Reviewed
• [Presentation] Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment E-poster (2020)
  • Author(s): Annan DA, Maishi N, Soga T, Dawood RIH, Li C, Kikuchi H, Hojo T, Morimoto M, Kitamura T, Alam MT, Minowa K, Shinohara N, Nam JM, Hida Y, Hida K
  • Organizer: The 21st International Vascular Biology Meeting (IVBM 2020)
  • Int'l Joint Research
• [Presentation] Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment (2020)
  • Author(s): Annan DA, Maishi N, Soga T, Dawood RIH, Li C, Kikuchi H, Hojo T, Morimoto M, Kitamura T, Alam MT, Minowa K, Shinohara N, Nam JM, Hida Y and Hida K
  • Organizer: 第6回北海道大学部局横断シンポジウム“若手研究者による生命と物質の融合を目指して！
• [Presentation] Glutamine metabolism facilitates tumor endothelial cell proliferation via redox homeostasis (2020)
  • Author(s): Annan DA, Maishi N, Soga T, Hojo T, Hida Y, Hida K
  • Organizer: The 79th Annual Meeting og the Japanese Cancer Association