Elucidation of the anticancer drug resistant mechanisms in colorectal cancer using a global lipid analysis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K16537
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: HIRAIDE TAKANORI 浜松医科大学, 医学部, 特任助教 (70780386)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 抗がん剤耐性 / 脂質 / 飽和脂肪酸 / 質量分析

Outline of Final Research Achievements

Resistance to chemotherapy is a major obstacle for the patients with unresectable colorectal cancer, although what factors induce chemoresistance is yet to be elucidated. The aim of this study was to examine whether lipid composition affects sensitivity to chemotherapeutic agents.
Lipidomic analysis using colorectal cancer xenograft-derived spheroid model revealed that saturated fatty acids (SFA)-containing lipids were abundant in spheroid showing chemoresistance to 5-fluorouracil (5-FU). To confirm the importance of SFA-containing lipids in chemoresistance, In in vitro model using colorectal cancer cell lines, genetic or pharmacological inactivation of stearoyl-CoA desaturase-1 (SCD1), the key enzyme converting SFA to mono unsaturated fatty acids (MUFA), increased SFA proportion in membranous lipids and decreased cell membrane fluidity, resulting in chemoresistance to 5-FU. The ratio of SFA/MUFA in cellular membranous lipids affects the sensitivity to chemotherapeutic agents.

Free Research Field

消化器外科

Academic Significance and Societal Importance of the Research Achievements

集学的治療により大腸癌の生命予後は改善されているものの、依然として我が国の癌死亡の上位を占めている。予後の向上には、発見時や術後再発時における転移・浸潤のコントロールと薬剤耐性回避が鍵であり、本研究は脂質の観点から抗癌剤耐性機構を調べた。
その結果、細胞膜内の飽和脂肪酸含有量の違いが、抗がん剤5-FUへの薬剤耐性をもたらすことが明らかになり、今までの抗がん剤耐性の観点とは異なり、がん細胞における膜脂質の病態生理への関与解明や癌治療への応用が期待できる。