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Originally published In Press as doi:10.1074/jbc.M207176200 on September 17, 2002

J. Biol. Chem., Vol. 277, Issue 47, 44988-44995, November 22, 2002
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Activation of Rac1 and the p38 Mitogen-activated Protein Kinase Pathway in Response to Arsenic Trioxide*

Amit VermaDagger §, Mani MohindruDagger , Dilip K. Deb§, Antonella SassanoDagger §, Suman KambhampatiDagger §, Farhad Ravandi§, Saverio Minucci, Dhananjaya V. Kalvakolanu||, and Leonidas C. PlataniasDagger §**

From the Dagger  Robert H. Lurie Comprehensive Cancer Center and Section of Hematology-Oncology, Northwestern University Medical School, Chicago, Illinois 60611, § Department of Medicine, Section of Hematology-Oncology, University of Illinois at Chicago and West Side Veterans Affairs Hospital, Chicago, Illinois 60607,  Department of Experimental Oncology, European Institute of Oncology, Milan 20141, Italy, and || Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland 21201

Arsenic trioxide induces differentiation and apoptosis of malignant cells in vitro and in vivo, but the mechanisms by which such effects occur have not been elucidated. In the present study we provide evidence that arsenic trioxide induces activation of the small G-protein Rac1 and the alpha  and beta  isoforms of the p38 mitogen-activated protein (MAP) kinase in several leukemia cell lines. Such activation of Rac1 and p38-isoforms results in downstream engagement of the MAP kinase-activated protein kinase-2 and is enhanced by pre-treatment of cells with ascorbic acid. Interestingly, pharmacological inhibition of p38 potentiates arsenic-dependent apoptosis and suppression of growth of leukemia cell lines, suggesting that this signaling cascade negatively regulates induction of antileukemic responses by arsenic trioxide. Consistent with this, overexpression of a dominant-negative p38 mutant (p38beta AGF) enhances the antiproliferative effects of arsenic trioxide on target cells. To further define the relevance of activation of the Rac1/p38 MAP kinase pathway in the induction of arsenic-dependent antileukemic effects, studies were performed using bone marrows from patients with chronic myelogenous leukemia. Arsenic trioxide suppressed the growth of leukemic myeloid (CFU-GM) progenitors from such patients, whereas concomitant pharmacological inhibition of the p38 pathway enhanced its growth-suppressive effects. Altogether, these data provide evidence for a novel function of the p38 MAP kinase pathway, acting as a negative regulator of arsenic trioxide-induced apoptosis and inhibition of malignant cell growth.

* This work was supported by a Merit Review grant from the Department of Veterans Affairs (to L. C. P.) and by National Institutes of Health Grants CA77816 and CA94079 (to L. C. P.) and CA71401 and CA78282 (to D. V. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Robert H. Lurie Comprehensive Cancer Ctr., Northwestern University Medical School, 303 E. Chicago Ave., Olson Pavilion 8250, Chicago, IL 60611. Tel.: 312-503-4267; Fax: 312-908-1372; E-mail: l-platanias@northwestern.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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