Department of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China; Key Laboratory of Screening and Activity Evaluation of Targeted Drugs, Chongqing 400054, China.
Department of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing 400054, China; Key Laboratory of Screening and Activity Evaluation of Targeted Drugs, Chongqing 400054, China.
Biochem Pharmacol. 2022 Nov;205:115241. doi: 10.1016/j.bcp.2022.115241. Epub 2022 Sep 6.
The solute carrier family 7 member 11 (SLC7A11), an amino acid transporter protein is frequently overexpressed in human malignancies. The expression and activity of SLC7A11 is finely regulated by oncogenes and tumor suppressors in tumor cells through various mechanisms and is highly specific for cystine and glutamate. Cystine is mainly transported intracellularly by SLC7A11 in the tumor microenvironment (TME) and is involved in GSH synthesis, which leads to ferroptosis resistance in tumor cells and promotes tumorigenesis and progression. The downregulation of SLC7A11 presents a unique drug discovery opportunity for ferroptosis-related diseases. Experimental work has shown that the combination of targeting SLC7A11 and tumor immunotherapy triggers ferroptosis more potently. Moreover, immunotargeting of SLC7A11 increases the chemosensitivity of cancer stem cells to doxorubicin, suggesting that it may act as an adjuvant to chemotherapy. Thus, SLC7A11 could be a promising target to overcome resistance mechanisms in conventional cancer treatments. This review provides an overview of the regulatory network of SLC7A11 in the TME and progress in the development of SLC7A11 inhibitors. In addition, we summarize the cytotoxic effects of blocking SLC7A11 in cancer cells, cancer stem cells and immune cells.
溶质载体家族 7 成员 11（SLC7A11）是一种氨基酸转运蛋白，在人类恶性肿瘤中经常过度表达。SLC7A11 的表达和活性通过各种机制在肿瘤细胞中受到癌基因和肿瘤抑制因子的精细调节，对胱氨酸和谷氨酸具有高度特异性。胱氨酸主要通过肿瘤微环境（TME）中的 SLC7A11 进行细胞内转运，并参与 GSH 合成，导致肿瘤细胞对铁死亡的抵抗，促进肿瘤发生和进展。SLC7A11 的下调为与铁死亡相关的疾病提供了独特的药物发现机会。实验工作表明，靶向 SLC7A11 和肿瘤免疫治疗的联合使用更有效地触发铁死亡。此外，SLC7A11 的免疫靶向增加了癌症干细胞对阿霉素的化疗敏感性，表明它可能作为化疗的辅助剂。因此，SLC7A11 可能是克服常规癌症治疗中耐药机制的有前途的靶标。本文综述了 SLC7A11 在 TME 中的调控网络以及 SLC7A11 抑制剂的开发进展。此外，我们总结了阻断 SLC7A11 在癌细胞、癌症干细胞和免疫细胞中的细胞毒性作用。
