TY - JOUR
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
N1 - Publisher Copyright:
© 2019 American Chemical Society.
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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U2 - 10.1021/acs.jmedchem.9b01685
DO - 10.1021/acs.jmedchem.9b01685
M3 - Article
C2 - 31774672
AN - SCOPUS:85077126127
SN - 0022-2623
VL - 62
SP - 11348
EP - 11358
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -