Please use this identifier to cite or link to this item:
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.
ISSN: 09254439
DOI: 10.1016/j.bbadis.2020.165964
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

Show full item record


checked on Nov 17, 2022


checked on Nov 15, 2022

Page view(s)

checked on Sep 18, 2023


checked on Sep 18, 2023

Google ScholarTM




Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.