Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide.
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 (p38betaAGF) 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.
Verma
Amit
A
Robert H. Lurie Comprehensive Cancer Center and Section of Hematology-Oncology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Mohindru
Mani
M
Deb
Dilip K
DK
Sassano
Antonella
A
Kambhampati
Suman
S
Ravandi
Farhad
F
Minucci
Saverio
S
Kalvakolanu
Dhananjaya V
DV
Platanias
Leonidas C
LC
D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism* / Q000494:pharmacology; D001205:Ascorbic Acid / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D006131:Growth Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D000975:Antioxidants; D001152:Arsenicals; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D010087:Oxides; D011725:Pyridines; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; C093642:SB 203580; D001205:Ascorbic Acid; D000077237:Arsenic Trioxide