Abstract
Wnt signaling plays a critical role in embryonic development, and its deregulation is closely linked to the occurrence of a number of malignant tumors, including breast and colon cancer. The pathway also induces Snail-dependent epithelial-to-mesenchymal transition (EMT), which is responsible for tumor invasion and metastasis. In this study, we show that Wnt suppresses mitochondrial respiration and cytochrome C oxidase (COX) activity by inhibiting the expression of 3 COX subunits, namely, COXVIc, COXVIIa, and COXVIIc. We found that Wnt induced a glycolytic switch via increased glucose consumption and lactate production, with induction of pyruvate carboxylase (PC), a key enzyme of anaplerosis. In addition, Wnt-induced mitochondrial repression and glycolytic switching occurred through the canonical β-catenin/T-cell factor 4/Snail pathway. Short hairpin RNA-mediated knockdown of E-cadherin, a regulator of EMT, repressed mitochondrial respiration and induced a glycolytic switch via Snail activation, indicating that EMT may contribute to Wnt/Snail regulation of mitochondrial respiration and glucose metabolism. Together, our findings provide a new function for Wnt/Snail signaling in the regulation of mitochondrial respiration (via COX gene expression) and glucose metabolism (via PC gene expression) in tumor growth and progression.
Highlights
Wnt signaling plays an important role in multiple embryonic developmental processes, and its aberrant activation occurs in association with the development and progression of many human cancers, including breast and colon cancer [1,2,3]. b-Catenin plays a key role in the canonical Wnt pathway [1, 2]
We found that Wnt1, Wnt3a, and Snail commonly decreased mRNA levels of COXVIc, COXVIIa, and COXVIIc, some other genes, such as COXVIIb, COX18, and SCO2 are differentially regulated depending on stimuli (Supplementary Table S3)
Because the epithelial-to-mesenchymal transition (EMT) inducer Snail regulates mitochondrial respiration and the glycolytic switch, we examined whether EMT itself is linked to the regulation of mitochondrial respiration and the glycolytic switch
Summary
Wnt signaling plays an important role in multiple embryonic developmental processes, and its aberrant activation occurs in association with the development and progression of many human cancers, including breast and colon cancer [1,2,3]. b-Catenin plays a key role in the canonical Wnt pathway [1, 2]. In the absence of Wnt, cytosolic b-catenin is associated with a destruction complex containing axis inhibition protein 1/2 (Axin1/2), adenomatous polyposis coli (APC), and glycogen synthase kinase 3b (GSK3b). It is phosphorylated by GSK3b and is rapidly degraded by the ubiquitin-proteasome system. Authors' Affiliations: 1Department of Molecular Biology, College of Natural Sciences, 2Nanobiotechnology Center, Pusan National University, Pusan; 3Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon; and 4Research Center for Resistant Cells, Chosun University, Gwangju, Korea. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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