Bone marrow stromal cells protect myeloma cells from ferroptosis through GPX4 deSUMOylation
Hongmei Jiang, Qian Li, Xudan Yang, Linchuang Jia, Hao Cheng, Jingya Wang, Sheng Wang, Xin Li, Ying Xie, Jingjing Wang, Yixuan Wang, Meilin Hu, Jing Guo, Ziyi Peng, Mengqi Wang, Tiantian Li, Haifeng Zhao, Lijuan Wang, Zhiqiang Liu
Abstract
Bone marrow stromal cells (BMSCs) are vital for preventing chemotherapy induced apoptosis of multiple myeloma (MM), but roles and machinery in other forms of cell death have not been well elucidated. Here, using an in vitro BMSC-MM interacting model, we observed BMSCs protected MM cells from labile iron pool (LIP) and reactive oxygen species (ROS) triggered ferroptosis by elevating glutathione peroxidase 4 (GPX4). Mechanistically, direct interaction with BMSCs upregulated the expression of SUMO-specific protease 3 (SENP3) in MM cells through CD40/CD40L signaling pathway, and SENP3 de-conjugated SUMO2 at lysine 75 residue to stabilize GPX4 protein, thereby consuming ROS to obviate ferroptosis in MM cells from the Vk*MYC mouse model, as well as in CD138 + B220 - cells separated from the Cd40l fl/fl ;Prx1 Cre/+ mice (CD40-CKO) and Sumo2 knock out (SUMO2-KO) mice. Using the NOD- scid IL2Rgamma null (NSG) mouse based xenograft model and intra-bone MM growth model, we validated that target SENP3 enhanced the killing effect of GPX4 inhibitor RSL3, thereby reduced tumor burden, prolonged survival of mice, and alleviated bone disruption of mice bearing MM tumors. Our study deciphers the mechanism of BMSCs preventing MM cells from spontaneous ferroptosis, and clarifies the therapeutic potential of non-apoptosis strategies in managing refractory or relapsed MM patients. • BMSCs protect MM cells against labile iron pool triggered ferroptosis. • BMSCs upregulate the expression of SENP3 in MM cells via CD40/CD40L pathway. • SENP3 de-conjugates SUMO2 from K75 residue of GPX4 to stabilize GPX4.