Elucidation of the multidrug resistance mechanisms by estrogen-related receptor and development of novel therapeutic strategies in endometrial cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16774
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: KOKABU TETSUYA 京都府立医科大学, 医学(系)研究科(研究院), 助教 (80848490)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: エストロゲン受容体 / エストロゲン関連受容体 / 子宮体癌 / 化学療法抵抗性 / miRNA

Outline of Final Research Achievements

We previously reported that estrogen-related receptor α (ERRα) regulated tumor progression in endometrial cancer. In the present study, we generated anticancer drug-resistant cell lines using endometrial cancer cell lines (HEC-1A and Ishikawa) and elucidated the mechanism of chemo-resistance related with ERRα, ABCB1 and miR-9. Additionally, we focused on the tumor microenvironment. The nutrient-deprived condition provided cancer cells increased not only levels of GLUT, xCT, MCT, VEGF, HIF-1α, and ERRα, but also resistance to chemotherapy. On the other hand, xCT, which regulates reactive oxygen species, was upregulated both in the nutrient-deprived condition and in the chemo-resistant cells. xCT inhibition increased ROS levels and improved chemo-sensitivity. These results elucidate the mechanism of chemo-resistance in uterine endometrial cancer and suggest the novel molecular target for the chemo-resistant endometrial cancer.

Free Research Field

子宮体癌

Academic Significance and Societal Importance of the Research Achievements

本邦の子宮体癌患者は急激に増加しているが、予後不良な進行・再発例における治療成績は十分とは言えない。本研究は子宮体癌の腫瘍学的特徴であるホルモン依存性疾患に着目し、エストロゲン伝達系制御を糸口とした治療抵抗性獲得機序の解明と新規治療法提唱を目的とする。
我々はエストロゲン関連受容体（ERRα）が化学療法抵抗性獲得に密接に関与することを示し、またがん微小環境における治療抵抗性獲得機序を解明した。本研究結果は子宮体癌における治療抵抗性機序を解明し、従来の治療法と異なった側面からのアプローチによる、新規治療標的を想起させうるものである。