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Title: | P-cadherin induces anoikis-resistance of matrix-detached breast cancer cells by promoting pentose phosphate pathway and decreasing oxidative stress | Authors: | Sousa, Bárbara Pereira, Joana Marques, Ricardo Grilo, Luís F Pereira, Susana P Oliveira, Vilma Marisa Arrojado Soares Sardão Schmitt, Fernando Oliveira, Paulo J Paredes, Joana Cancela de Amorim Falcão |
Keywords: | Antioxidant; Breast cancer; Matrix-detached; Oxidative stress; P-cadherin; anoikis-resistant | Issue Date: | 2020 | Volume: | 1866 | Issue: | 12 | Abstract: | Successful metastatic spreading relies on cancer cells with stem-like properties, glycolytic metabolism and increased antioxidant protection, allowing them to escape anoikis and to survive in circulation. The expression of P-cadherin, a poor prognostic factor in breast cancer, is associated with hypoxic, glycolytic and acidosis biomarkers. In agreement, P-cadherin-enriched breast cancer cell populations presents a glycolytic and an acid-resistance phenotype. Our aim was to evaluate whether P-cadherin expression controls the glycolytic and oxidative phosphorylation fluxes of matrix-detached breast cancer cells, acting as an antioxidant and enhancing their survival in anchorage-independent conditions. By using matrix-detached breast cancer cells, we concluded that P-cadherin increases glucose-6-phosphate dehydrogenase expression, up-regulating the carbon flux through the pentose phosphate pathway, while inhibiting pyruvate oxidation to acetyl-coA via pyruvate dehydrogenase kinase-4 (PDK-4) activation. Accordingly, P-cadherin expression conferred increased sensitivity to dichloroacetate (DCA), a PDK inhibitor. P-cadherin expression also regulates oxidative stress in matrix-detached breast cancer cells, through the control of antioxidant systems, such as catalase and superoxide dismutases (SOD)1 and 2, providing these cells with an increased resistance to doxorubicin-induced anoikis. Importantly, this association was validated in primary invasive breast carcinomas, where an enrichment of SOD2 was found in P-cadherin-overexpressing breast carcinomas. In conclusion, we propose that P-cadherin up-regulates carbon flux through the pentose phosphate pathway and decreases oxidative stress in matrix-detached breast cancer cells. These metabolic remodeling and antioxidant roles of P-cadherin can promote the survival of breast cancer cells in circulation and in metastatic sites, being a possible player in breast cancer therapeutic resistance to pro-oxidant-based interventions. | URI: | https://hdl.handle.net/10316/101006 | ISSN: | 09254439 | DOI: | 10.1016/j.bbadis.2020.165964 | Rights: | openAccess |
Appears in Collections: | I&D CNC - Artigos em Revistas Internacionais |
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File | Description | Size | Format | |
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Sousa et al. - 2020 - Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease-annotated.pdf | 5.27 MB | Adobe PDF | View/Open |
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