The role of PKR in hepatocellular carcinoma associated with intracellular metabolism

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08388
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Ehime University
• Principal Investigator: Watanabe Takao 愛媛大学, 医学系研究科, 講師 (90650458)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 肝細胞癌 / PKR / 細胞増殖 / 代謝経路 / 阻害剤

Outline of Final Research Achievements

We have shown that PKR is highly expressed in hepatocellular carcinoma and that administration of imidazolo-oxindole, an inhibitor of PKR suppressed tumor growth. We also identified by mass spectrometry hexokinase -2, a major enzyme in glycolysis, as a target protein for PKR inhibitor. In hepatocellular carcinoma cell lines PKR inhibitor treatment suppressed HK2 expression. We showed that PKR and HK2 bind directly, which is dependent on PKR phosphorylation. PKR inhibitors suppressed intracellular ATP production by suppressing glycolysis. Overexpression of HK2 increased tumor proliferation and adding overexpression of PKR at the same time additively increased that. These findings suggest that PKR-HK2 axis increases tumor growth in hepatocellular carcinoma by promoting glycolysis, and that PKR-HK2 axis may be a novel therapeutic target in hepatocellular carcinoma.

Free Research Field

消化器内科

Academic Significance and Societal Importance of the Research Achievements

肝細胞癌における治療標的となる分子や経路はごく限られており、治療効果のエビデンスのある薬物は十分ではないのが現状である。我々は以前より肝細胞癌で高発現するPKRの役割、癌促進機序を研究してきた。本研究ではPKRが肝細胞癌の細胞内代謝に関わる複数の分子に影響を与えていることを見出した。その中で特に解糖系の主要分子であるHK2に着目し研究を行い、PKR-HK2経路が解糖系の促進を介して腫瘍増殖能を亢進していることを見出した。このことは細胞内代謝経路の変化という新たな視点での治療標的になり得ると考えられた。