Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.

Autor: Erazo-Oliveras A; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX, 77843, USA., Muñoz-Vega M; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX, 77843, USA., Mlih M; Department of Cell Biology and Genetics, Texas A&M University, School of Medicine, Bryan, TX, 77807, USA., Thiriveedi V; Department of Medicine, Division of Gastroenterology, Duke University School of Medicine, Durham, NC, 27710, USA.; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.; Department of Cell Biology, Duke University School of Medicine, Durham, NC, 27710, USA., Salinas ML; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX, 77843, USA., Rivera-Rodríguez JM; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX, 77843, USA., Kim E; Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Denver, CO, 80045, USA., Wright RC; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA., Wang X; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA., Landrock KK; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA., Goldsby JS; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX, 77843, USA., Mullens DA; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX, 77843, USA., Roper J; Department of Medicine, Division of Gastroenterology, Duke University School of Medicine, Durham, NC, 27710, USA.; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.; Department of Cell Biology, Duke University School of Medicine, Durham, NC, 27710, USA., Karpac J; Department of Cell Biology and Genetics, Texas A&M University, School of Medicine, Bryan, TX, 77807, USA., Chapkin RS; Program in Integrative Nutrition and Complex Diseases, Texas A&M University, College Station, TX, 77843, USA. r-chapkin@tamu.edu.; Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA. r-chapkin@tamu.edu.; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, TX, 77843, USA. r-chapkin@tamu.edu.; Center for Environmental Health Research, Texas A&M University, College Station, TX, 77843, USA. r-chapkin@tamu.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Jul 19; Vol. 14 (1), pp. 4342. Date of Electronic Publication: 2023 Jul 19.
DOI: 10.1038/s41467-023-39640-w
Abstrakt: Although the role of the Wnt pathway in colon carcinogenesis has been described previously, it has been recently demonstrated that Wnt signaling originates from highly dynamic nano-assemblies at the plasma membrane. However, little is known regarding the role of oncogenic APC in reshaping Wnt nanodomains. This is noteworthy, because oncogenic APC does not act autonomously and requires activation of Wnt effectors upstream of APC to drive aberrant Wnt signaling. Here, we demonstrate the role of oncogenic APC in increasing plasma membrane free cholesterol and rigidity, thereby modulating Wnt signaling hubs. This results in an overactivation of Wnt signaling in the colon. Finally, using the Drosophila sterol auxotroph model, we demonstrate the unique ability of exogenous free cholesterol to disrupt plasma membrane homeostasis and drive Wnt signaling in a wildtype APC background. Collectively, these findings provide a link between oncogenic APC, loss of plasma membrane homeostasis and CRC development.
(© 2023. The Author(s).)
Databáze: MEDLINE
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