Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide

Amit K. Verma, Mani Mohindru, Dilip K. Deb, Antonella Sassano, Suman Kambhampati, Farhad Ravandi, Saverio Minucci, Dhananjaya V. Kalvakolanul, Leonidas C. Platanias

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Abstract

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 α and β 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 (p38βAGF) 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.

Original languageEnglish (US)
Pages (from-to)44988-44995
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number47
DOIs
StatePublished - Nov 22 2002
Externally publishedYes

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p38 Mitogen-Activated Protein Kinases
Chemical activation
Cells
Arsenic
Apoptosis
Growth
Protein Isoforms
Leukemia
Pharmacology
Cell Line
Granulocyte-Macrophage Progenitor Cells
Monomeric GTP-Binding Proteins
Cell growth
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Mitogen-Activated Protein Kinases
Protein Kinases
Ascorbic Acid
arsenic trioxide
Bone
Bone Marrow

ASJC Scopus subject areas

  • Biochemistry

Cite this

Verma, A. K., Mohindru, M., Deb, D. K., Sassano, A., Kambhampati, S., Ravandi, F., ... Platanias, L. C. (2002). Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide. Journal of Biological Chemistry, 277(47), 44988-44995. https://doi.org/10.1074/jbc.M207176200

Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide. / Verma, Amit K.; Mohindru, Mani; Deb, Dilip K.; Sassano, Antonella; Kambhampati, Suman; Ravandi, Farhad; Minucci, Saverio; Kalvakolanul, Dhananjaya V.; Platanias, Leonidas C.

In: Journal of Biological Chemistry, Vol. 277, No. 47, 22.11.2002, p. 44988-44995.

Research output: Contribution to journalArticle

Verma, AK, Mohindru, M, Deb, DK, Sassano, A, Kambhampati, S, Ravandi, F, Minucci, S, Kalvakolanul, DV & Platanias, LC 2002, 'Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide', Journal of Biological Chemistry, vol. 277, no. 47, pp. 44988-44995. https://doi.org/10.1074/jbc.M207176200
Verma, Amit K. ; Mohindru, Mani ; Deb, Dilip K. ; Sassano, Antonella ; Kambhampati, Suman ; Ravandi, Farhad ; Minucci, Saverio ; Kalvakolanul, Dhananjaya V. ; Platanias, Leonidas C. / Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 47. pp. 44988-44995.
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AU - Ravandi, Farhad

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