Pecchillo Cimmino Tiziana, Punziano Carolina, Panico Iolanda, Petrone Zeudi, Cassese Myrhiam, Faraonio Raffaella, Barresi Vincenza, Esposito Gabriella, Ammendola Rosario, Cattaneo Fabio
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.
Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.
Antioxidants (Basel). 2024 Apr 30;13(5):552. doi: 10.3390/antiox13050552.
Cancer cells exhibit high levels of oxidative stress and consequently require a high amount of cysteine for glutathione synthesis. Solute Carrier Family 7 Member 11 (SLC7A11), or xCT, mediates the cellular uptake of cystine in exchange for intracellular glutamate; imported extracellular cystine is reduced to cysteine in the cytosol through a NADPH-consuming reduction reaction. SLC7A11/xCT expression is under the control of stress-inducing conditions and of several transcription factors, such as NRF2 and ATF4. Formyl-peptide receptor 2 (FPR2) belongs to the FPR family, which transduces chemotactic signals mediating either inflammatory or anti-inflammatory responses according to the nature of its ligands and/or FPR2 binding with other FPR isoforms. The repertoire of FPR2 agonists with anti-inflammatory activities comprises WKYMVm peptide and Annexin A1 (ANXA1), and the downstream effects of the intracellular signaling cascades triggered by FPR2 include NADPH oxidase (NOX)-dependent generation of reactive oxygen species. Herein, we demonstrate that stimulation of CaLu-6 cells with either WKYMVm or ANXA1: (i) induces the redox-regulated activation of SLC7A11/xCT; (ii) promotes the synthesis of glutathione; (iii) prevents lipid peroxidation; and (iv) favors NRF2 nuclear translocation and activation. In conclusion, our overall results demonstrate that FPR2 agonists and NOX modulate SLC7A11/xCT expression and activity, thereby identifying a novel regulative pathway of the cystine/glutamate antiport that represents a new potential therapeutical target for the treatment of human cancers.
癌细胞表现出高水平的氧化应激，因此需要大量的半胱氨酸来合成谷胱甘肽。溶质载体家族7成员11（SLC7A11），即xCT，介导细胞摄取胱氨酸以交换细胞内谷氨酸；导入的细胞外胱氨酸通过消耗NADPH的还原反应在细胞质中还原为半胱氨酸。SLC7A11/xCT的表达受应激诱导条件和几种转录因子（如NRF2和ATF4）的控制。甲酰肽受体2（FPR2）属于FPR家族，根据其配体的性质和/或FPR2与其他FPR异构体的结合，转导介导炎症或抗炎反应的趋化信号。具有抗炎活性的FPR2激动剂包括WKYMVm肽和膜联蛋白A1（ANXA1），由FPR2触发的细胞内信号级联反应的下游效应包括依赖NADPH氧化酶（NOX）产生活性氧。在此，我们证明用WKYMVm或ANXA1刺激CaLu-6细胞：（i）诱导SLC7A11/xCT的氧化还原调节激活；（ii）促进谷胱甘肽的合成；（iii）防止脂质过氧化；（iv）促进NRF2核转位和激活。总之，我们的总体结果表明，FPR2激动剂和NOX调节SLC7A11/xCT的表达和活性，从而确定了胱氨酸/谷氨酸反向转运体的一种新的调节途径，这代表了治疗人类癌症的一个新的潜在治疗靶点。
