Reversal of bortezomib resistance in myelodysplastic syndrome cells by MAPK inhibitors

PLoS One. 2014 Mar 7;9(3):e90992. doi: 10.1371/journal.pone.0090992. eCollection 2014.

Abstract

The myelodysplastic syndromes (MDS) comprise a heterogeneous group of malignant neoplasms with distinctive clinicopathological features. Currently, there is no specific approach for the treatment of MDS. Here, we report that bortezomib (BTZ), a proteasome inhibitor that has been used to treat plasma cell myeloma, induced G2/M phase cycle arrest in the MDS cell line SKM-1 through upregulation of Wee1, a negative regulator of G2/M phase transition. Treatment by BTZ led to reduced SKM-1 cell viability as well as increased apoptosis and autophagy. The BTZ-induced cell death was associated with reduced expression of p-ERK. To elucidate the implications of downregulation of p-ERK, we established the BTZ resistant cell line SKM-1R. Our data show that resistance to BTZ-induced apoptosis could be reversed by the MEK inhibitors U0126 or PD98059. Our results suggest that MAPK pathway may play an important role in mediating BTZ resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Bone Marrow Cells / drug effects*
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Boronic Acids / pharmacology
  • Bortezomib
  • Butadienes / pharmacology
  • Cell Cycle Proteins / agonists
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • G2 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • MAP Kinase Signaling System
  • Nitriles / pharmacology
  • Nuclear Proteins / agonists
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Proteasome Inhibitors / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Pyrazines / pharmacology

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • Butadienes
  • Cell Cycle Proteins
  • Flavonoids
  • Nitriles
  • Nuclear Proteins
  • Proteasome Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazines
  • U 0126
  • Bortezomib
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Grants and funding

This work was supported by the project for the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.