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

Wen Zhang; Vitaliy M. Sviripa; Liliia M. Kril; Tianxin Yu; Yanqi Xie; W. Brad Hubbard; Patrick G. Sullivan; Xi Chen; Chang Guo Zhan; Yang Yang-Hartwich; B. Mark Evers; Brett T. Spear; Roberto Gedaly; David S. Watt; Chunming Liu

doi:10.1021/acs.jmedchem.9b01685

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

Wen Zhang, Vitaliy M. Sviripa, Liliia M. Kril, Tianxin Yu, Yanqi Xie, W. Brad Hubbard, Patrick G. Sullivan, Xi Chen, Chang Guo Zhan, Yang Yang-Hartwich, B. Mark Evers, Brett T. Spear, Roberto Gedaly, David S. Watt, Chunming Liu

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English
Pages (from-to)	11348-11358
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	24
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01685
State	Published - Dec 26 2019

Bibliographical note

Publisher Copyright:
© 2019 American Chemical Society.

Funding

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).

Funders	Funder number
Center for Pharmaceutical Research and Innovation in the College of Pharmacy
College of Medicine
College of Pharmacy, the Department of Defense
Dean of the
NIH P30	P30 CA177558
Office of the Chief
University of Kentucky’s Graduate School
National Institutes of Health (NIH)	NIH UL1 TR000117
U.S. Department of Defense	W81XWH-16-1-0635, P30 RR020171, 150326P2
American Cancer Society	SRF
National Institute of General Medical Sciences	IRG 16-182-28
Center for Clinical and Translational Science, University of Illinois at Chicago
University of Kentucky Markey Cancer Center

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Zhang, W., Sviripa, V. M., Kril, L. M., Yu, T., Xie, Y., Hubbard, W. B., Sullivan, P. G., Chen, X., Zhan, C. G., Yang-Hartwich, Y., Evers, B. M., Spear, B. T., Gedaly, R., Watt, D. S., & Liu, C. (2019). An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors. Journal of Medicinal Chemistry, 62(24), 11348-11358. https://doi.org/10.1021/acs.jmedchem.9b01685

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

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.",

author = "Wen Zhang and Sviripa, {Vitaliy M.} and Kril, {Liliia M.} and Tianxin Yu and Yanqi Xie and Hubbard, {W. Brad} and Sullivan, {Patrick G.} and Xi Chen and Zhan, {Chang Guo} and Yang Yang-Hartwich and Evers, {B. Mark} and Spear, {Brett T.} and Roberto Gedaly and Watt, {David S.} and Chunming Liu",

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doi = "10.1021/acs.jmedchem.9b01685",

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Zhang, W, Sviripa, VM, Kril, LM, Yu, T, Xie, Y, Hubbard, WB , Sullivan, PG, Chen, X, Zhan, CG, Yang-Hartwich, Y, Evers, BM , Spear, BT , Gedaly, R, Watt, DS & Liu, C 2019, 'An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation: Mitochondrial Uncouplers Masquerading as Wnt Inhibitors', Journal of Medicinal Chemistry, vol. 62, no. 24, pp. 11348-11358. https://doi.org/10.1021/acs.jmedchem.9b01685

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T1 - An Underlying Mechanism of Dual Wnt Inhibition and AMPK Activation

T2 - Mitochondrial Uncouplers Masquerading as Wnt Inhibitors

AU - Zhang, Wen

AU - Sviripa, Vitaliy M.

AU - Kril, Liliia M.

AU - Yu, Tianxin

AU - Xie, Yanqi

AU - Hubbard, W. Brad

AU - Sullivan, Patrick G.

AU - Chen, Xi

AU - Zhan, Chang Guo

AU - Yang-Hartwich, Yang

AU - Evers, B. Mark

AU - Spear, Brett T.

AU - Gedaly, Roberto

AU - Watt, David S.

AU - Liu, Chunming

PY - 2019/12/26

Y1 - 2019/12/26

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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