IGFs & Metabolic Endocrinology Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Bristol BS10 5NB, UK.
School of Allied Health Professions, Faculty of Health Sciences, University of Botswana, Gaborone, Plot 4775, Botswana.
Int J Mol Sci. 2020 Nov 17;21(22):8674. doi: 10.3390/ijms21228674.
Hyperglycaemia is a common metabolic alteration associated with breast cancer risk and progression. We have previously reported that BRCA1 restrains metabolic activity and proliferative response to IGF-I anabolic actions in breast cancer cells cultured in high glucose. Here, we evaluated the impact of normal physiological glucose on these tumour suppressive roles of BRCA1. Human breast cancer cells cultured in normal physiological and high glucose were treated with IGF-I (0-500 ng/mL). Cellular responses were evaluated using immunoblotting, co-immunoprecipitation, and cell viability assay. As we previously reported, IGF-I induced ACCA dephosphorylation by reducing the association between BRCA1 and phosphorylated ACCA in high glucose, and upregulated FASN abundance downstream of ACCA. However, these effects were not observed in normal glucose. Normal physiological glucose conditions completely blocked IGF-I-induced ACCA dephosphorylation and FASN upregulation. Co-immunoprecipitation studies showed that normal physiological glucose blocked ACCA dephosphorylation by increasing the association between BRCA1 and phosphorylated ACCA. Compared to high glucose, the proliferative response of breast cancer cells to IGF-I was reduced in normal glucose, whereas no difference was observed in normal mammary epithelial cells. Considering these results collectively, we conclude that normal physiological glucose promotes the novel function of BRCA1 as a metabolic restraint of IGF-I actions. These data suggest that maintaining normal glucose levels may improve BRCA1 function in breast cancer and slow down cancer progression.
高血糖是一种与乳腺癌风险和进展相关的常见代谢改变。我们之前曾报道过 BRCA1 可抑制乳腺癌细胞在高葡萄糖培养条件下对 IGF-I 合成代谢作用的代谢活性和增殖反应。在这里，我们评估了正常生理葡萄糖对 BRCA1 这些肿瘤抑制作用的影响。在正常生理和高葡萄糖中培养的人乳腺癌细胞用 IGF-I（0-500ng/ml）处理。使用免疫印迹、共免疫沉淀和细胞活力测定评估细胞反应。正如我们之前报道的，IGF-I 通过减少 BRCA1 与高葡萄糖中磷酸化 ACCA 的结合，诱导 ACCA 去磷酸化，并上调 ACCA 下游的 FASN 丰度。然而，在正常葡萄糖中没有观察到这些作用。正常生理葡萄糖条件完全阻断了 IGF-I 诱导的 ACCA 去磷酸化和 FASN 上调。共免疫沉淀研究表明，正常生理葡萄糖通过增加 BRCA1 与磷酸化 ACCA 的结合，促进了 ACCA 的去磷酸化。与高葡萄糖相比，乳腺癌细胞对 IGF-I 的增殖反应在正常葡萄糖中降低，而在正常乳腺上皮细胞中则没有差异。综合这些结果，我们得出结论，正常生理葡萄糖促进了 BRCA1 作为 IGF-I 作用的代谢抑制因子的新功能。这些数据表明，维持正常血糖水平可能会改善乳腺癌中 BRCA1 的功能，并减缓癌症的进展。
