Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 62, Issue 24, Pages 11348-11358Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.9b01685
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Funding
- NIH from the National Institutes of Health [R01 CA172379, UL1 TR000117, P30 CA177558]
- Office of the Dean of the College of Medicine
- Center for Pharmaceutical Research and Innovation in the College of Pharmacy
- Department of Defense (DoD Prostate Cancer Research Program) [W81XWH-16-1-0635, PC150326P2]
- NIH from the National Institute of General Medical Sciences [P30 RR020171]
- grant IRG from the American Cancer Society [16-182-28]
- Markey Cancer Center [P30 CA177558]
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The importance of upregulated Wnt signaling in colorectal cancers led to efforts to develop inhibitors that target beta-catenin in this pathway. We now report that several Wnt inhibitors that allegedly target beta-catenin actually function as mitochondrial proton uncouplers that independently activate AMPK and concomitantly inhibit Wnt signaling. As expected for a process in which mitochondrial uncoupling diminishes ATP production, a mitochondrial proton uncoupler, FCCP, and a glucose metabolic inhibitor, 2-DG, activated AMPK and inhibited Wnt signaling. Also consistent with these findings, a well-known Wnt inhibitor, FH535, functioned as a proton uncoupler, and in support of this finding, the N-methylated analog, 2,5-dichloro-N-methyl-N-(2-methy1-4-nitrophenyl)-benzenesulfonamide (FH535-M), was inactive as an uncoupler and Wnt inhibitor. Apart from suggesting an opportunity to develop dual Wnt inhibitors and AMPK activators, these findings provide a cautionary tale that claims for Wnt inhibition alone require scrutiny as possible mitochondrial proton uncouplers or inhibitors of the electron transport chain.
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