Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal.
Oxid Med Cell Longev. 2019 Jul 11;2019:2061830. doi: 10.1155/2019/2061830. eCollection 2019.
Breast cancer is the major cause of tumor-associated mortality in women worldwide, with prognosis depending on the early discovery of the disease and on the type of breast cancer diagnosed. Among many factors, lipids could contribute to breast cancer malignancy by participating in cellular processes. Also, aquaporins are membrane channels found aberrantly expressed in cancer tissues that were correlated with tumor aggressiveness, progression, and metastasis. However, the differences in lipid profile and aquaporin expression between cell types of different malignant potential have never been investigated. Here, we selected three breast cancer cell lines representing the three major breast cancer types (hormone positive, HER2 positive, and triple negative) and analyzed their lipid profile and steady state lipid hydroperoxide levels to correlate with cell sensitivity to HO. Additionally, the expression profiles of AQP1, AQP3, and AQP5 and the Nrf2 transcription factor were evaluated, before and after oxidative challenge. We found that the lipid profile was dependent on the cell type, with the HER2-positive cells having the lowest level PUFA, whereas the triple negative showed the highest. However, in triple-negative cancer cells, a lower level of the Nrf2 may be responsible for a higher sensitivity to HO challenge. Interestingly, HER2-positive cells showed the highest increase in intracellular ROS after oxidative challenge, concomitant with a significantly higher level of AQP1, AQP3, and AQP5 expression compared to the other cell types, with AQP3 always being the most expressed isoform. The AQP3 gene expression was stimulated by HO treatment in hormone-positive and HER2 cells, together with Nrf2 expression, but was downregulated in triple-negative cells that showed instead upregulation of AQP1 and AQP5. The lipid profile and AQP gene expression after oxidative challenge of these particularly aggressive cell types may represent metabolic reprogramming of cancer cells and reflect a role in adaptation to stress and therapy resistance.
乳腺癌是全球女性肿瘤相关死亡的主要原因，其预后取决于疾病的早期发现和诊断的乳腺癌类型。在许多因素中，脂质可能通过参与细胞过程而导致乳腺癌的恶性程度增加。此外，水通道蛋白是在癌症组织中异常表达的膜通道，与肿瘤侵袭性、进展和转移相关。然而，不同恶性潜能的细胞类型之间的脂质谱和水通道蛋白表达的差异从未被研究过。在这里，我们选择了三种乳腺癌细胞系，代表三种主要的乳腺癌类型（激素阳性、HER2 阳性和三阴性），并分析了它们的脂质谱和稳态脂质氢过氧化物水平，以与细胞对 HO 的敏感性相关。此外，还评估了 AQP1、AQP3 和 AQP5 的表达谱以及 Nrf2 转录因子的表达谱，在氧化应激前后。我们发现，脂质谱依赖于细胞类型，HER2 阳性细胞的多不饱和脂肪酸（PUFA）水平最低，而三阴性细胞的脂质谱则最高。然而，在三阴性乳腺癌细胞中，较低水平的 Nrf2 可能导致对 HO 挑战的更高敏感性。有趣的是，HER2 阳性细胞在氧化应激后显示出最高的细胞内 ROS 增加，与其他细胞类型相比，AQP1、AQP3 和 AQP5 的表达水平显著升高，AQP3 始终是表达最丰富的同工型。AQP3 基因的表达在激素阳性和 HER2 细胞中被 HO 处理刺激，与 Nrf2 表达一起，但在三阴性细胞中被下调，这些细胞表现出 AQP1 和 AQP5 的上调。这些特别侵袭性细胞类型在氧化应激后的脂质谱和 AQP 基因表达可能代表癌细胞的代谢重编程，并反映了对压力和治疗耐药性的适应作用。
