Hsp90 Inhibitor SNX-7081 dysregulates proteins involved with DNA repair and replication and the cell cycle in human chronic lymphocytic leukemia (CLL) cells

Yiping Che, O. Giles Best, Ling Zhong, Kimberley L. Kaufman, Swetlana Mactier, Mark Raftery, Lee M. Graves, Stephen P. Mulligan, Richard I. Christopherson

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

The proteomic effects of the Hsp90 inhibitor, SNX-7081, have been determined on the p53-mutated B-cell chronic lymphocytic leukemia (CLL) cell line, MEC1. Following SNX-7081 treatment (500 nM, 24 h), 51 proteins changed abundance by more than 2-fold (p < 0.05); 7 proteins increased while 44 proteins decreased. Proteins identified as differentially abundant by LC-MS/MS were validated by Western blotting (DDB1, PCNA, MCM2, Hsp90, Hsp70, GRP78, PDIA6, HLA-DR). RT-PCR showed that SNX-7081 unexpectedly modulates a number of these proteins in MEC1 cells at the mRNA level (PCNA, MCM2, Nup155, Hsp70, GRP78, PDIA6, and HLA-DR). Pathway analysis determined that 3 of the differentially abundant proteins (cyclin D1, c-Myc and pRb) were functionally related. p53 levels did not change upon SNX-7081 treatment of p53 wild-type Raji cells or p53-mutated MEC1 and U266 cells, indicating that SNX-7081 has a p53-independent mechanism. The decreases in DDB1, MCM2, c-Myc, and PCNA and increases of pRb and cyclin D1 were confirmed in MEC1, U266, Raji, and p53 null HL60 cells by Western blotting. These data suggest that SNX-7081 arrests the cell cycle and inhibits DNA replication and r epair and provides evidence for the mechanism of the observed synergy between Hsp90 inhibitors and drugs that induce DNA strand breaks.
Original languageEnglish
Pages (from-to)1710-1722
Number of pages13
JournalJournal of Proteome Research
Volume12
Issue number4
DOIs
Publication statusPublished - 4 Mar 2013
Externally publishedYes

Keywords

  • Apoptosi
  • metabolism Reproducibility of Results Tandem Mass Spectrometry
  • genetics
  • analysis
  • Pathology Proteome
  • metabolism
  • drug therapy
  • B-Cell
  • Chronic
  • Lymphocytic
  • metabolism Humans Leukemia
  • antagonists & inhibitors
  • drug effects Genes p53 HSP90 Heat-Shock Proteins
  • drug effects DNA Replication
  • drug effects Cell Line, Tumor DNA Repair
  • pharmacology Cell Cycle
  • drug effects Benzamides

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