Formyl-Peptide Receptor 2 Signaling Modulates SLC7A11/xCT Expression and Activity in Tumor Cells

被引:0
|
作者
Cimmino, Tiziana Pecchillo [1 ]
Punziano, Carolina [1 ]
Panico, Iolanda [1 ]
Petrone, Zeudi [1 ]
Cassese, Myrhiam [1 ]
Faraonio, Raffaella [1 ]
Barresi, Vincenza [2 ]
Esposito, Gabriella [1 ]
Ammendola, Rosario [1 ]
Cattaneo, Fabio [1 ]
机构
[1] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, I-80131 Naples, Italy
[2] Univ Catania, Dept Biomed & Biotechnol Sci, I-95123 Catania, Italy
关键词
formyl-peptide receptor 2; NADPH oxidase; glutathione; lipid peroxidation; NRF2; CYSTINE/GLUTAMATE ANTIPORTER; MOLECULAR-MECHANISMS; SYSTEM X(C)(-); NADPH OXIDASES; NOX FAMILY; CANCER; ROS; LOCALIZATION; PEROXIDATION; FERROPTOSIS;
D O I
10.3390/antiox13050552
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:18
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