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P-cadherin induces anoikis-resistance of matrix-detached breast cancer cells by promoting pentose phosphate pathway and decreasing oxidative stress.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ( IF 4.2 ) Pub Date : 2020-09-10 , DOI: 10.1016/j.bbadis.2020.165964
Bárbara Sousa 1 , Joana Pereira 1 , Ricardo Marques 2 , Luís F Grilo 2 , Susana P Pereira 2 , Vilma A Sardão 2 , Fernando Schmitt 3 , Paulo J Oliveira 2 , Joana Paredes 3
Affiliation  

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.



中文翻译:

P-钙粘着蛋白通过促进戊糖磷酸途径和减少氧化应激诱导基质分离的乳腺癌细胞的抗凋亡。

成功的转移扩散依赖于具有干细胞样特性,糖酵解代谢和增强的抗氧化剂保护能力的癌细胞,使它们能够逃脱失灵并在循环中生存。P-钙粘着蛋白的表达是乳腺癌预后不良的因素,它与低氧,糖酵解和酸中毒生物标志物有关。一致地,富含P-钙黏着蛋白的乳腺癌细胞群呈现出糖酵解和耐酸表型。

我们的目的是评估P-钙粘着蛋白表达是否控制基质分离的乳腺癌细胞的糖酵解和氧化磷酸化通量,充当抗氧化剂并增强其在不依赖锚固条件下的存活率。通过使用基质分离的乳腺癌细胞,我们得出结论,P-钙黏着蛋白增加葡萄糖-6-磷酸脱氢酶的表达,上调通过戊糖磷酸途径的碳通量,同时抑制丙酮酸通过丙酮酸脱氢酶激酶4氧化为乙酰辅酶A。 (PDK-4)激活。因此,P-钙黏着蛋白的表达赋予了对PDK抑制剂二氯乙酸盐(DCA)的敏感性。P-钙粘蛋白的表达还通过控制抗氧化系统(例如过氧化氢酶和超氧化物歧化酶(SOD)1和2)来调节基质分离的乳腺癌细胞中的氧化应激。anoikis。重要的是,这种关联在原发性浸润性乳腺癌中得到了验证,在P-钙粘蛋白过表达的乳腺癌中发现了SOD2的富集。

总之,我们提出P-钙黏着蛋白上调通过戊糖磷酸途径的碳通量,并降低基质分离的乳腺癌细胞中的氧化应激。P-钙黏着蛋白的这些代谢重塑和抗氧化作用可以促进乳腺癌细胞在循环和转移部位的存活,可能是乳腺癌对基于氧化剂的干预治疗的抵抗力。

更新日期:2020-09-25
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