PLoS ONE (Jan 2014)

Reversal of bortezomib resistance in myelodysplastic syndrome cells by MAPK inhibitors.

  • Yingxing Yue,
  • Ying Wang,
  • Yang He,
  • Shuting Yang,
  • Zixing Chen,
  • Yuanyuan Wang,
  • Shanshan Xing,
  • Congcong Shen,
  • Hesham M Amin,
  • Depei Wu,
  • Yao-Hua Song

DOI
https://doi.org/10.1371/journal.pone.0090992
Journal volume & issue
Vol. 9, no. 3
p. e90992

Abstract

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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.