An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors

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.