The importance of upregulated Wnt signaling in colorectal cancers led to efforts to develop inhibitors that target β-catenin in this pathway. We now report that several "Wnt inhibitors" that allegedly target β-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-methyl-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.

Original languageEnglish
Pages (from-to)11348-11358
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number24
StatePublished - Dec 26 2019

Bibliographical note

Funding Information:
We are grateful to Professor Randall Moon for the Super 8x TOPFlash and 8x FOPFlash plasmids. C.L. and D.S.W. were supported by NIH R01 CA172379 from the National Institutes of Health and NIH UL1 TR000117 from the National Institutes of Health to the University of Kentucky’s Center for Clinical and Translational Science. B.M.E. was supported by NIH P30 CA177558 from the National Institutes of Health. D.S.W. was also supported in part by the Office of the Dean of the College of Medicine, the Center for Pharmaceutical Research and Innovation in the College of Pharmacy, the Department of Defense (DoD Prostate Cancer Research Program Award W81XWH-16-1-0635 [grant log #PC150326P2]), and NIH P30 RR020171 from the National Institute of General Medical Sciences to L. Hersh. V.M.S. was supported by grant IRG 16-182-28 from the American Cancer Society). The Redox Metabolism Shared Resource Facility (RM SRF) that performed the Seahorse XF studies is supported by Markey Cancer Center (P30 CA177558).

Publisher Copyright:
© 2019 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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