12-O-tetradecanoylphorbol-13-acetate (TPA)-induced dual-specificity phosphatase expression and AML cell survival

Dale G Schaar; Hao Liu; Shashi Sharma; Yi Ting; John Martin; Curtis Krier; Marie Ciardella; Mona Osman; Lauri Goodell; Daniel A Notterman; Roger K Strair

doi:10.1016/j.leukres.2005.02.019

12-O-tetradecanoylphorbol-13-acetate (TPA)-induced dual-specificity phosphatase expression and AML cell survival

Leuk Res. 2005 Oct;29(10):1171-9. doi: 10.1016/j.leukres.2005.02.019. Epub 2005 Apr 11.

Authors

Dale G Schaar¹, Hao Liu, Shashi Sharma, Yi Ting, John Martin, Curtis Krier, Marie Ciardella, Mona Osman, Lauri Goodell, Daniel A Notterman, Roger K Strair

Affiliation

¹ The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey (UMDNJ), NJ, USA. schaardg@umdnj.edu

PMID: 16111535
DOI: 10.1016/j.leukres.2005.02.019

Abstract

12-O-Tetradecanoylphorbol-13-acetate (TPA) is being developed as a therapeutic agent by virtue of its being a potent modulator of signal transduction in pre-clinical models of AML [Strair RK, Schaar D, Goodell L, Aisner J, Chin KV, Eid J, et al. Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate. Clin Cancer Res 2002;8:2512-8]. In this report, we identify a subset of primary AML samples that undergoes apoptosis after exposure to TPA and demonstrate that TPA-induced cytotoxicity is associated with modulation of the ERK signaling pathway. Analysis of mitogen-activated protein kinase (MAPK) dual-specificity phosphatases (DUSP), as potential regulators of AML cell signaling, indicates that these genes are coordinately regulated and rapidly induced by TPA in primary AML cells. Therefore, TPA-induced primary AML cytotoxicity is associated with modulation of ERK signaling which may be partially mediated by regulation of phosphatase expression.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Acute Disease
Apoptosis / drug effects
Blotting, Western
Carcinogens / pharmacology*
Cell Cycle Proteins / metabolism*
Cell Survival
Dual Specificity Phosphatase 1
Gene Expression Profiling
Humans
Immediate-Early Proteins / metabolism*
Leukemia, Myeloid / drug therapy
Leukemia, Myeloid / enzymology*
Leukemia, Myeloid / pathology
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / metabolism*
Oligonucleotide Array Sequence Analysis
Phosphoprotein Phosphatases / metabolism*
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology
Protein Phosphatase 1
Protein Tyrosine Phosphatases / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects*
Tetradecanoylphorbol Acetate / pharmacology*

Substances

Carcinogens
Cell Cycle Proteins
Immediate-Early Proteins
Protein Kinase Inhibitors
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Phosphoprotein Phosphatases
Protein Phosphatase 1
DUSP1 protein, human
Dual Specificity Phosphatase 1
Protein Tyrosine Phosphatases
Tetradecanoylphorbol Acetate