ALCAM regulates multiple myeloma chemoresistant side population

Fangfang Wang, Zhang Dan, Hongmei Luo, Jingcao Huang, Yushan Cui, Hong Ding, Juan Xu, Zhimei Lin, Yuhan Gao, Xinyu Zhai, Yan Yang, Ying Qu, Li Zhang, Fengjiao Chen, Qiang Wang, Xin Wang, Yu Feng, Ting Liu, Qing Yi, Ting NiuYuhuan Zheng

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number136
Pages (from-to)136
JournalCell Death and Disease
Volume13
Issue number2
DOIs
StatePublished - Feb 10 2022

Keywords

  • Activated-Leukocyte Cell Adhesion Molecule/metabolism
  • Animals
  • Antigens, CD
  • Cell Adhesion Molecules, Neuronal
  • Cell Line, Tumor
  • Epidermal Growth Factor
  • ErbB Receptors/genetics
  • Fetal Proteins
  • Hedgehog Proteins
  • Humans
  • Mice
  • Multiple Myeloma/drug therapy

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cancer Research
  • Cell Biology
  • Immunology

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