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An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt
Wen Zhang, Vitaliy M Sviripa, Liliia M Kril
1Department of Obstetrics, Gynecology and Reproductive Sciences , Yale School of Medicine , LSOG 209, 375 Congress Avenue , New Haven Connecticut 06510 , United States.
Abstract:
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.
Insights
Several Wnt inhibitors targeting colorectal cancer actually uncouple mitochondria, activating AMPK and inhibiting Wnt signaling. This suggests a need to scrutinize Wnt inhibition claims for potential mitochondrial effects.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Wnt signaling is crucial in colorectal cancer, prompting the development of β-catenin targeting inhibitors.
- Existing Wnt inhibitors require further investigation for their precise mechanisms of action.
Purpose of the Study:
- To investigate the mechanism of action of several purported Wnt inhibitors.
- To determine if these compounds exhibit off-target effects on cellular metabolism.
Main Methods:
- Assessed the effect of Wnt inhibitors on mitochondrial function and AMPK activation.
- Utilized FCCP and 2-DG as controls for mitochondrial uncoupling and metabolic inhibition.
- Compared the activity of FH535 with its N-methylated analog, FH535-M.
Main Results:
- Several "Wnt inhibitors" were identified as mitochondrial proton uncouplers.
- Mitochondrial uncoupling and metabolic inhibition led to AMPK activation and Wnt signaling inhibition.
- FH535 demonstrated proton uncoupling activity, while its analog FH535-M did not.
Conclusions:
- Wnt inhibitors may act as mitochondrial proton uncouplers, independently activating AMPK.
- Findings highlight the need for scrutiny of Wnt inhibition claims, considering potential mitochondrial effects.
- This research opens avenues for developing dual Wnt inhibitors and AMPK activators.
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