Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells

J Interferon Cytokine Res. 2020 Aug;40(8):389-405. doi: 10.1089/jir.2020.0111. Epub 2020 Jul 23.

Abstract

[Figure: see text] Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan-Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine substitution (rs3779620) slightly suppresses the tumor formation. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3 as well as caspase activities. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.

Keywords: PBK; interleukin-6; molecular-targeted therapy; multiple myeloma; tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Gene Editing
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Genetic Loci
  • Humans
  • Interleukin-6 / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / genetics*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / mortality
  • Multiple Myeloma / pathology
  • Phosphorylation
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • STAT3 Transcription Factor
  • Transcriptome

Substances

  • Interleukin-6
  • Protein Kinase Inhibitors
  • STAT3 Transcription Factor
  • Mitogen-Activated Protein Kinase Kinases
  • PDZ-binding kinase