Inhibition of protein phosphatase-1 and -2A decreases the chemosensitivity of leukemic cells to chemotherapeutic drugs

Dóra Dedinszki, Andrea Kiss, László Márkász, Adrienn Márton, Emese Tóth, László Székely, Ferenc Erdodi

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The phosphorylation of key proteins balanced by protein kinases and phosphatases are implicated in the regulation of cell cycle and apoptosis of malignant cells and influences anticancer drug actions. The efficacy of daunorubicin (DNR) in suppression of leukemic cell survival was investigated in the presence of tautomycin (TM) and calyculin A (CLA), specific membrane permeable inhibitors of protein phosphatase-1 (PP1) and -2A (PP2A), respectively. CLA (50. nM) or TM (1. μM) suppressed viability of THP-1 and KG-1 myeloid leukemia cell lines to moderate extents; however, they significantly increased survival upon DNR-induced cell death. CLA increased the phosphorylation level of Erk1/2 and PKB/Akt kinases, the retinoblastoma protein (pRb), decreased caspase-3 activation by DNR and increased the phosphorylation level of the inhibitory sites (Thr696 and Thr853) in the myosin phosphatase (MP) target subunit (MYPT1) as well as in a 25. kDa kinase-enhanced phosphatase inhibitor (KEPI)-like protein. TM induced enhanced phosphorylation of pRb only, suggesting that this event may be a common factor upon CLA-induced PP2A and TM-induced PP1 inhibitory influences on cell survival. Silencing PP1 by siRNA in HeLa cells, or overexpression of Flag-KEPI in MCF-7 cells coupled with inducing its phosphorylation by PMA or CLA, resulted in increased phosphorylation of pRb. Our results indicate that PP1 directly dephosphorylates pRb, while PP2A might have an indirect influence via mediating the phosphorylation level of PP1 inhibitory proteins. These data imply the importance of PP1 inhibitory proteins in controlling the phosphorylation state of key proteins and regulating drug sensitivity and apoptosis in leukemic cells.

Original languageEnglish
Pages (from-to)363-372
Number of pages10
JournalCellular Signalling
Volume27
Issue number2
DOIs
Publication statusPublished - Feb 1 2015

Keywords

  • Daunorubicin
  • KG-1 leukemic cells
  • Kinase-enhanced protein inhibitor (KEPI) of protein phosphatase-1
  • Protein phosphatase-1 and -2A
  • Retinoblastoma protein
  • THP-1

ASJC Scopus subject areas

  • Cell Biology

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