| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| 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.
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