Stromal cells attenuate the cytotoxicity of imatinib on Philadelphia chromosome-positive leukemia cells by up-regulating the VE-cadherin/β-catenin signal

Leuk Res. 2014 Dec;38(12):1460-8. doi: 10.1016/j.leukres.2014.09.012. Epub 2014 Oct 8.

Abstract

β-Catenin is a key regulator of leukemia stem cell maintenance and drug resistance. Herein, we investigated the protective effects of the stromal cell-mediated VE-cadherin-β-catenin signal on Ph+ leukemia cells during imatinib treatment. We found stromal cells could desensitize imatinib and up-regulate VE-cadherin expression on Ph+ leukemia cells (K562 and SUP-B15 cells), which further stabilized and activated β-catenin. Knockdown of VE-cadherin with shRNA diminished the β-catenin protein and partly resensitized Ph+ leukemia cells to imatinib despite the presence of stromal cells, suggesting VE-cadherin is a potential target in the treatment of Ph+ leukemia.

Keywords: Imatinib; Ph+ leukemia; Stromal cells; VE-cadherin; β-Catenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / biosynthesis*
  • Antineoplastic Agents / pharmacology*
  • Benzamides / pharmacology*
  • Cadherins / biosynthesis*
  • Cell Line, Tumor
  • Coculture Techniques
  • Drug Resistance, Neoplasm / drug effects*
  • Gene Expression Regulation, Leukemic / drug effects*
  • Humans
  • Imatinib Mesylate
  • K562 Cells
  • Leukemia / drug therapy*
  • Leukemia / metabolism
  • Leukemia / pathology
  • Neoplasm Proteins / biosynthesis*
  • Philadelphia Chromosome*
  • Piperazines / pharmacology*
  • Pyrimidines / pharmacology*
  • Signal Transduction / drug effects*
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Up-Regulation / drug effects
  • beta Catenin / biosynthesis*

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • Benzamides
  • Cadherins
  • Neoplasm Proteins
  • Piperazines
  • Pyrimidines
  • beta Catenin
  • cadherin 5
  • Imatinib Mesylate