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Research Articles: Therapeutics, Targets, and Development

Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling

Departments of ¹ Biochemistry, ² Medicine, and ³ Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia; ⁴ Departments of Pathology, Neurosurgery and Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York; ⁵ Division of Human Gene Therapy, Departments of Medicine, Pathology and Surgery, and the Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Birmingham, Alabama; and ⁶ Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Paul Dent, Department of Biochemistry, Virginia Commonwealth University, 401 College Street, Massey Cancer Center, Box 980035, Richmond, VA 23298-0035. Phone: 804-628-0861; Fax: 804-827-1309. E-mail: pdent{at}vcu.edu

Abstract

The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH₂-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function. [Mol Cancer Ther 2008;7(2):314–29]

Grant support: Public Health Service grants P01-CA104177, R01-CA108325, and R01-DK52825, Jim Valvano "V" Foundation, and Department of Defense award DAMD17-03-1-0262 (P. Dent); Public Health Service grants R01-CA63753 and R01-CA77141 and a Leukemia Society of America grant 6405-97 (S. Grant); Public Health Service grant P01-CA104177 (D.T. Curiel); and Public Health Service grants P01-CA104177, R01-CA97318, R01-CA98172, and P01-NS31492, Samuel Waxman Cancer Research Foundation, and Michael and Stella Chernow Endowment (P.B. Fisher).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: P. Dent is The Universal, Inc. Professor in Signal Transduction Research and P.B. Fisher is The Michael and Stella Chernow Urological Cancer Research Scientist.

⁷ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 10/ 1/07; revised 11/26/07; accepted 12/ 1/07.

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