AI Article Synopsis
- The study investigates how the enzyme PMVK from the mevalonate metabolic pathway enhances β-catenin signaling, which is often disrupted in cancer.
- PMVK stabilizes β-catenin by preventing its degradation and promoting its movement into the cell nucleus, leading to increased cancer-promoting activity.
- Deleting PMVK in mouse models hinders embryonic development but its inhibition using a small molecule, PMVKi5, shows promise in reducing liver and colorectal cancer, highlighting a potential therapeutic target.
Article Abstract
β-catenin signaling is abnormally activated in cancer. Here, this work screens the mevalonate metabolic pathway enzyme PMVK to stabilize β-catenin signaling using a human genome-wide library. On the one hand, PMVK-produced MVA-5PP competitively binds to CKIα to prevent β-catenin Ser45 phosphorylation and degradation. On the other hand, PMVK functions as a protein kinase to directly phosphorylate β-catenin Ser184 to increase its protein nuclear localization. This synergistic effect of PMVK and MVA-5PP together promotes β-catenin signaling. In addition, PMVK deletion impairs mouse embryonic development and causes embryonic lethal. PMVK deficiency in liver tissue alleviates DEN/CCl -induced hepatocarcinogenesis. Finally, the small molecule inhibitor of PMVK, PMVKi5, is developed and PMVKi5 inhibits carcinogenesis of liver and colorectal tissues. These findings reveal a non-canonical function of a key metabolic enzyme PMVK and a novel link between the mevalonate pathway and β-catenin signaling in carcinogenesis providing a new target for clinical cancer therapy.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10131864 | PMC |
| http://dx.doi.org/10.1002/advs.202204909 | DOI Listing |
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