Exploring biological basis of aberrant energy metabolic property of gastrointestinal cancer toward application to cancer treatment

2015 Fiscal Year Final Research Report

• Project/Area Number: 25860233
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Kanazawa University
• Principal Investigator: Domoto Takahiro 金沢大学, がん進展制御研究所, 助教 (80635540)
• Research Collaborator: MINAMOTO TOSHINARI 金沢大学, がん進展制御研究所, 教授 (50239323)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: がん代謝 / 分子標的治療 / リン酸化 / GSK3beta

Outline of Final Research Achievements

We have identified aberrant GSK3beta as an attractive therapeutic target in various cancer types. Here we explored the mechanism for the tumor-promoting role of GSK3beta by focusing on the distinct energy metabolic property in cancer. We found that GSK3beta deregulated in cancer cells and their xenografts phosphorylates and inactivates pyruvate dehydrogenase (PDH)-E1alpha, the active subunit of PDH. This results in induction of the aerobic glycolysis that preferentially fuels cancer cells, leading to progression of cancer. Inhibition of GSK3beta shifted the energy source of cancer cells from glycolysis to oxidative phosphorylation in mitochondria, rendering them susceptible to apoptotic insults. No such metabolic changes were observed in non-neoplastic cells or rodent’s liver. Our results suggests that cancer therapeutic effect of GSK3beta inhibition depends on the exclusive metabolic shift in cancer cells, which reinforces the safety of targeting GSK3beta for cancer treatment.

Free Research Field

医歯薬学