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Updated: Oct 21, 2025

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DKK1 activates noncanonical NF-κB signaling via IL-6-induced CKAP4 receptor in multiple myeloma

Xin Li1, Jingjing Wang1, Shuai Zhu1

  • 1Department of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Heping, Tianjin, China.

Blood Advances
|September 1, 2021
PubMed

Insights

Dickkopf-1 (DKK1) promotes bortezomib resistance in multiple myeloma (MM) by downregulating CD138 and activating the NF-κB pathway via CKAP4. Targeting the DKK1-CKAP4 axis improves treatment sensitivity and reduces bone destruction.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Proteasome inhibitors like bortezomib (BTZ) are crucial for multiple myeloma (MM) treatment.
  • Acquired chemoresistance and relapse are significant challenges in MM therapy.

Purpose of the Study:

  • To identify key cytokines involved in bortezomib resistance in MM.
  • To elucidate the mechanism by which Dickkopf-1 (DKK1) contributes to MM chemoresistance.
  • To explore therapeutic strategies targeting the DKK1 pathway.

Main Methods:

  • Screening of differentially expressed cytokines in BTZ-resistant MM cells.
  • In vitro experiments assessing DKK1's effect on myeloma cell resistance and CD138 expression.
  • Investigation of DKK1-CKAP4 interaction and downstream signaling pathways (Wnt, NF-κB).
  • Evaluation of DKK1-CKAP4 axis antagonism in a mouse model of MM.

Main Results:

  • DKK1 levels were significantly increased, while CD138 levels were decreased in BTZ-resistant MM cells.
  • DKK1 enhanced myeloma cell resistance to BTZ, suppressing CD138 via Wnt signaling inhibition.
  • DKK1 induced resistance through the CKAP4 receptor, activating the NF-κB pathway.
  • Interleukin-6 (IL-6) stimulated CKAP4 expression, contributing to drug resistance.
  • Disrupting the DKK1-CKAP4 axis improved BTZ sensitivity and reduced bone destruction in a mouse model.

Conclusions:

  • DKK1 plays a critical role in MM drug resistance through both Wnt-dependent and independent mechanisms.
  • The DKK1-CKAP4 axis, influenced by IL-6, is a key mediator of bortezomib resistance in MM.
  • Antagonism of the DKK1-IL-6 loop represents a promising therapeutic strategy for overcoming MM chemoresistance and mitigating bone disease.

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