Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Biological Chemistry, Graduate School of Science, Osaka Metropolitan University, Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
J Biochem. 2024 Mar 4;175(3):313-322. doi: 10.1093/jb/mvad105.
The cystine/glutamate transporter SLC7A11/xCT is highly expressed in many cancer cells and plays an important role in antioxidant activity by supplying cysteine for glutathione synthesis. Under glucose-depleted conditions, however, SLC7A11-mediated cystine uptake causes oxidative stress and cell death called disulfidptosis, a new form of cell death. We previously reported that high cell density (HD) promotes lysosomal degradation of SLC7A11 in glioblastoma cells, allowing them to survive under glucose-depleted conditions. In this study, we found that the neurofibromatosis type 2 gene, Merlin/NF2 is a key regulator of SLC7A11 in glioblastoma cells at HD. Deletion of Merlin increased SLC7A11 protein level and cystine uptake at HD, leading to promotion of cell death under glucose deprivation. Furthermore, HD significantly decreased SLC7A11 mRNA level, which was restored by Merlin deletion. This study suggests that Merlin suppresses glucose deprivation-induced cell death by downregulating SLC7A11 expression in glioblastoma cells at HD.
胱氨酸/谷氨酸转运蛋白 SLC7A11/xCT 在许多癌细胞中高度表达，通过为谷胱甘肽合成提供半胱氨酸来发挥重要的抗氧化活性。然而，在葡萄糖缺乏的情况下，SLC7A11 介导的胱氨酸摄取会导致氧化应激和细胞死亡，称为二硫键凋亡，这是一种新的细胞死亡形式。我们之前曾报道，高密度（HD）促进神经纤维瘤病 2 型基因 Merlin/NF2 在神经胶质瘤细胞中的溶酶体降解，使它们能够在葡萄糖缺乏的条件下存活。在这项研究中，我们发现 Merlin 是神经胶质瘤细胞中 SLC7A11 的关键调节因子。Merlin 的缺失增加了 SLC7A11 蛋白水平和 HD 时的胱氨酸摄取，导致在葡萄糖剥夺下促进细胞死亡。此外，HD 显著降低 SLC7A11 mRNA 水平，而 Merlin 缺失则恢复了这一水平。这项研究表明，Merlin 通过下调神经胶质瘤细胞在 HD 时的 SLC7A11 表达来抑制葡萄糖剥夺诱导的细胞死亡。
