Research Paper Volume 15, Issue 16 pp 8220—8236

Inhibition of VCP modulates NF-κB signaling pathway to suppress multiple myeloma cell proliferation and osteoclast differentiation

Rongfang Wei1, *, , Yuhao Cao1, *, , Hongjie Wu1, , Xin Liu1, , Mingmei Jiang1, , Xian Luo1, , Zhendong Deng1, , Ze Wang1, , Mengying Ke1, , Yongqiang Zhu2, , Siqing Chen3, , Chunyan Gu1, , Ye Yang1, ,

  • 1 School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
  • 2 College of Life Science, Nanjing Normal University, Nanjing, China
  • 3 Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
* Equal contribution and share first authorship

Received: May 8, 2023       Accepted: July 20, 2023       Published: August 21, 2023
How to Cite

Copyright: © 2023 Wei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Multiple myeloma (MM) is the second most common hematological malignancy, in which the dysfunction of the ubiquitin-proteasome pathway is associated with the pathogenesis. The valosin containing protein (VCP)/p97, a member of the AAA+ ATPase family, possesses multiple functions to regulate the protein quality control including ubiquitin-proteasome system and molecular chaperone. VCP is involved in the occurrence and development of various tumors while still elusive in MM. VCP inhibitors have gradually shown great potential for cancer treatment. This study aims to identify if VCP is a therapeutic target in MM and confirm the effect of a novel inhibitor of VCP (VCP20) on MM. We found that VCP was elevated in MM patients and correlated with shorter survival in clinical TT2 cohort. Silencing VCP using siRNA resulted in decreased MM cell proliferation via NF-κB signaling pathway. VCP20 evidently inhibited MM cell proliferation and osteoclast differentiation. Moreover, exosomes containing VCP derived from MM cells partially alleviated the inhibitory effect of VCP20 on cell proliferation and osteoclast differentiation. Mechanism study revealed that VCP20 inactivated the NF-κB signaling pathway by inhibiting ubiquitination degradation of IκBα. Furthermore, VCP20 suppressed MM cell proliferation, prolonged the survival of MM model mice and improved bone destruction in vivo. Collectively, our findings suggest that VCP is a novel target in MM progression. Targeting VCP with VCP20 suppresses malignancy progression of MM via inhibition of NF-κB signaling pathway.


MM: Multiple myeloma; VCP: valosin containing protein; ERAD: retention of endoplasmic reticulum-associated degradation; UPR: unfolded protein response; GEP: The Gene expression profiling; FBS: fetal bovine serum; siRNA: Small interfering RNA; NC: negative control; RNA-seq: RNA-sequencing; MOE: Molecular Operating Environment; BMD: bone mineral density; BV/TV: bone volume / total volume; TT2: Total Therapy 2; NF-κB: NF-kappa B; EMT: Epithelial-mesenchymal transition; PDB: Paget's disease of bone.