School of Life Science, Northwestern Polytechnical University, Xi'an, 710072, PR China; Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, B-1090, Belgium.
Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, B-1090, Belgium.
Cancer Lett. 2022 Jun 1;535:215649. doi: 10.1016/j.canlet.2022.215649. Epub 2022 Mar 18.
Multiple myeloma (MM) cells derive proliferative signals from the bone marrow (BM) microenvironment via exosomal crosstalk. Therapeutic strategies targeting this crosstalk are still lacking. Bortezomib resistance in MM cells is linked to elevated expression of xCT (the subunit of system Xc). Extracellular glutamate released by system Xc can bind to glutamate metabotropic receptor (GRM) 3, thereby upregulating Rab27-dependent vesicular trafficking. Since Rab27 is also involved in exosome biogenesis, we aimed to investigate the role of system Xc in exosomal communication between BM stromal cells (BMSCs) and MM cells. We observed that expression of xCT and GRMs was increased after bortezomib treatment in both BMSCs and MM cells. Secretion of glutamate and exosomes was simultaneously enhanced which could be countered by inhibition of system Xc or GRMs. Moreover, glutamate supplementation increased exosome secretion by increasing expression of Alix, TSG101, Rab27a/b and VAMP7. Importantly, the system Xc inhibitor sulfasalazine reduced BMSC-induced resistance to bortezomib in MM cells in vitro and enhanced its anti-MM effects in vivo. These findings suggest that system Xc plays an important role within the BM and could be a potential target in MM.
多发性骨髓瘤（MM）细胞通过外泌体通讯从骨髓（BM）微环境中获得增殖信号。针对这种通讯的治疗策略仍然缺乏。MM 细胞对硼替佐米的耐药性与 xCT（系统 Xc 的亚基）表达升高有关。系统 Xc 释放的细胞外谷氨酸可以与谷氨酸代谢型受体（GRM）3 结合，从而上调 Rab27 依赖性囊泡转运。由于 Rab27 也参与外泌体的生物发生，我们旨在研究系统 Xc 在 BM 基质细胞（BMSC）和 MM 细胞之间的外泌体通讯中的作用。我们观察到，硼替佐米处理后，BMSC 和 MM 细胞中 xCT 和 GRM 的表达均增加。谷氨酸的分泌和外泌体的分泌同时增强，这可以通过抑制系统 Xc 或 GRM 来抵消。此外，谷氨酸补充通过增加 Alix、TSG101、Rab27a/b 和 VAMP7 的表达来增加外泌体的分泌。重要的是，系统 Xc 抑制剂柳氮磺胺吡啶可减少体外 BMSC 诱导的 MM 细胞对硼替佐米的耐药性，并增强其体内抗 MM 作用。这些发现表明，系统 Xc 在 BM 中发挥重要作用，可能是 MM 的一个潜在靶点。
