Pyk2 promotes tumor progression in multiple myeloma

Blood. 2014 Oct 23;124(17):2675-86. doi: 10.1182/blood-2014-03-563981. Epub 2014 Sep 12.

Abstract

Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared with healthy individuals. By using loss-of-function approaches, we found that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cell-cycle progression, and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/β-catenin signaling by destabilizing β-catenin, leading to downregulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718 effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology*
  • Animals
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Disease Progression
  • Female
  • Focal Adhesion Kinase 2 / antagonists & inhibitors*
  • Focal Adhesion Kinase 2 / genetics
  • Focal Adhesion Kinase 2 / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Luminescent Measurements
  • Mice, SCID
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / prevention & control*
  • Protein Kinase Inhibitors / pharmacology*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Analysis
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Wnt Signaling Pathway / drug effects
  • Xenograft Model Antitumor Assays*
  • beta Catenin / metabolism

Substances

  • Aminopyridines
  • PND 1186
  • Protein Kinase Inhibitors
  • beta Catenin
  • Green Fluorescent Proteins
  • Focal Adhesion Kinase 2