Resistance to phorbol 12-myristate 13-acetate-induced cell growth arrest in an HL60 cell line chronically exposed to a glutathione S-transferase pi inhibitor

Biochemical Pharmacology
Laurent GatéK D Tew

Abstract

Glutathione S-transferase pi (GSTpi; EC 2.5.1.18) has been shown recently to be a regulator of mitogen-activated protein kinases (MAPK). We have developed, by chronic exposure of HL60 cells to increasing concentrations of a peptidomimetic GSTpi inhibitor TLK199, a 10-fold resistant cell line (HL60/TLK199). Among the cellular adaptations observed in this cell line was an increase in extracellular signal-regulated kinase (ERK) activity without modification of basal expression levels. Phorbol 12-myristate 13-acetate (PMA) induced monocyte/macrophage cytodifferentiation in both HL60 wild-type (WT) and HL60/TLK199 cells. In contrast, PMA induced a pronounced cell growth inhibition and G(0)/G(1) cell cycle arrest in HL60 WT cells, while this differentiating agent had only a mild effect on cell growth without G(0)/G(1) cell cycle arrest in HL60/TLK199. This effect was associated with a rapid and sustained activation of ERK (up to 6hr) in HL60 WT cells but only a transient induction of these kinases (between 30 and 60min) in HL60/TLK199. Furthermore, treatment of both cell lines with PMA in combination with the protein tyrosine phosphatase inhibitors sodium orthovanadate (OV) or 3,4-dephostatin (DPN) circumvented the resistance to cell...Continue Reading

References

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Citations

Aug 6, 2009·Apoptosis : an International Journal on Programmed Cell Death·Fang HeTong Wang
Jan 31, 2004·Current Oncology Reports·David Hamilton, Gerald Batist

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