TY - JOUR
T1 - ALCAM regulates multiple myeloma chemoresistant side population
AU - Wang, Fangfang
AU - Dan, Zhang
AU - Luo, Hongmei
AU - Huang, Jingcao
AU - Cui, Yushan
AU - Ding, Hong
AU - Xu, Juan
AU - Lin, Zhimei
AU - Gao, Yuhan
AU - Zhai, Xinyu
AU - Yang, Yan
AU - Qu, Ying
AU - Zhang, Li
AU - Chen, Fengjiao
AU - Wang, Qiang
AU - Wang, Xin
AU - Feng, Yu
AU - Liu, Ting
AU - Yi, Qing
AU - Niu, Ting
AU - Zheng, Yuhuan
N1 - Funding Information:
This work was supported by grants to YZ from the National Natural Science Foundation of China (Nos. 81870157, 82070219, and 81670188), and the Sichuan University Faculty Start Fund. This work was also supported by grants to TN from Incubation Program for Clinical Trials (No. 19HXFH030), Achievement Transformation Project (No. CGZH21001), 1-3-5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC21007), and Translational Research Grant of NCRCH (No. 2021WWB03)
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/2
Y1 - 2022/2
N2 - Drug-resistance is a major problem preventing a cure in patients with multiple myeloma (MM). Previously, we demonstrated that activated-leukocyte-cell-adhesion-molecule (ALCAM) is a prognostic factor in MM and inhibits EGF/EGFR-initiated MM clonogenicity. In this study, we further showed that the ALCAM-EGF/EGFR axis regulated the MM side population (SP)-mediated drug-resistance. ALCAM-knockdown MM cells displayed an enhanced ratio of SP cells in the presence of bone marrow stromal cells (BMSCs) or with the supplement of recombinant EGF. SP MM cells were resistant to chemotherapeutics melphalan or bortezomib. Drug treatment stimulated SP-genesis. Mechanistically, EGFR, primed with EGF, activated the hedgehog pathway and promoted the SP ratio; meanwhile, ALCAM inhibited EGFR downstream pro-MM cell signaling. Further, SP MM cells exhibited an increased number of mitochondria compared to the main population. Interference of the mitochondria function strongly inhibited SP-genesis. Animal studies showed that combination therapy with both an anti-MM agent and EGFR inhibitor gefitinib achieved prolonged MM-bearing mice survival. Hence, our work identifies ALCAM as a novel negative regulator of MM drug-resistance, and EGFR inhibitors may be used to improve MM therapeutic efficacy.
AB - Drug-resistance is a major problem preventing a cure in patients with multiple myeloma (MM). Previously, we demonstrated that activated-leukocyte-cell-adhesion-molecule (ALCAM) is a prognostic factor in MM and inhibits EGF/EGFR-initiated MM clonogenicity. In this study, we further showed that the ALCAM-EGF/EGFR axis regulated the MM side population (SP)-mediated drug-resistance. ALCAM-knockdown MM cells displayed an enhanced ratio of SP cells in the presence of bone marrow stromal cells (BMSCs) or with the supplement of recombinant EGF. SP MM cells were resistant to chemotherapeutics melphalan or bortezomib. Drug treatment stimulated SP-genesis. Mechanistically, EGFR, primed with EGF, activated the hedgehog pathway and promoted the SP ratio; meanwhile, ALCAM inhibited EGFR downstream pro-MM cell signaling. Further, SP MM cells exhibited an increased number of mitochondria compared to the main population. Interference of the mitochondria function strongly inhibited SP-genesis. Animal studies showed that combination therapy with both an anti-MM agent and EGFR inhibitor gefitinib achieved prolonged MM-bearing mice survival. Hence, our work identifies ALCAM as a novel negative regulator of MM drug-resistance, and EGFR inhibitors may be used to improve MM therapeutic efficacy.
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U2 - 10.1038/s41419-022-04556-8
DO - 10.1038/s41419-022-04556-8
M3 - Article
C2 - 35145058
AN - SCOPUS:85124446934
VL - 13
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 2
M1 - 136
ER -