Arsenic inhibition of the JAK-STAT pathway (original) (raw)
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A redox-linked novel pathway for arsenic-mediated RET tyrosine kinase activation
Journal of Cellular Biochemistry, 2010
We examined the biochemical effects of arsenic on the activities of RET proto-oncogene (c-RET protein tyrosine kinases) and RET oncogene (RET-MEN2A and RET-PTC1 protein tyrosine kinases) products. Arsenic activated c-RET kinase with promotion of disulfide bond-mediated dimerization of c-RET protein. Arsenic further activated RET-MEN2A kinase, which was already 3- to 10-fold augmented by genetic mutation compared with c-RET kinase activity, with promotion of disulfide bond-mediated dimerization of RET-MEN2A protein (superactivation). Arsenic also increased extracellular domain-deleted RET-PTC1 kinase activity with promotion of disulfide bond-mediated dimerization of RET-PTC1 protein. Arsenic increased RET-PTC1 kinase activity with cysteine 365 (C365) replaced by alanine with promotion of dimer formation but not with cysteine 376 (C376) replaced by alanine. Our results suggest that arsenic-mediated regulation of RET kinase activity is dependent on conformational change of RET protein through modulation of a special cysteine sited at the intracellular domain in RET protein (relevant cysteine of C376 in RET-PTC1 protein). Moreover, arsenic enhanced the activity of immunoprecipitated RET protein with increase in thiol-dependent dimer formation. As arsenic (14.2 µM) was detected in the cells cultured with arsenic (100 µM), direct association between arsenic and RET in the cells might modulate dimer formation. Thus, we demonstrated a novel redox-linked mechanism of activation of arsenic-mediated RET proto-oncogene and oncogene products. J. Cell. Biochem. 110: 399–407, 2010. © 2010 Wiley-Liss, Inc.
Journal of Cellular Biochemistry, 2002
Chronic exposure to low levels of arsenic can cause lung cancer. However, the cellular and molecular mechanisms for lung cell transformation in response to arsenic are not known. These studies investigated the hypothesis that low levels of arsenic increase intracellular oxidant levels, promote production of mitogenic transcription factors and antioxidant enzymes. Initially, arsenic decreased GSH cellular level and rapidly increased to 280% of GSH level in nonexposed lung cells in 24 h. Buthionine sulfoximine (BSO) potentiated the arsenic toxicity of lung epithelial cells (LEC). Exposure of LEC to 5 μM arsenite cause time-dependent increase in γ-glutamylcysteine synthetase (γ-GCS) expression. Our data demonstrated that arsenic induced the heavy subunit of γ-GCS (γ-GCS-HS) mRNA levels as early as 4 h as compared to the control level. It significantly increased (sixfolds) γ-GCS-HS mRNA expression after 8 h of treatment. The activation of AP-1 transcription factors may also play a regulatory role in this process. Significant elevations in c-fos and c-jun mRNA levels were observed within 30 min after exposure to arsenic and by enhancement of AP-1 DNA binding activity and transactivation activity. Responsiveness of LEC to oxidative stress caused by arsenic exposure was further evaluated with mobility shift assay involving redox-sensitive transcription factor NF-κB. The specificity of binding was verified by an antibody-supershift. The NF-κB DNA binding activities increased more than twofold 30 min after exposure to arsenic and returned to control levels after 4 h of treatment. It remains to be determined whether NF-κB plays a role in the As-induced apoptosis or alternatively in attempting to protect the cells from As-induced cell death by upregulating the expression of resistance factors. J. Cell. Biochem. 87: 29–38, 2002. © 2002 Wiley-Liss, Inc.
Main Group Metal Chemistry
Arsenic (As) is a semi-metal which causes health problems in human, and immune system has been documented as one of the main target of arsenic toxicity. Apoptosis has a crucial role in regulation of immune system, but it can also have an important role in As immune suppression. So, we decided to assess the comprehensive mechanism of As cytotoxic effect on lymphocytes isolated from human blood. We determine the direct effect of arsenic on human lymphocytes which have a key role in immune system functionality. To evaluate the mechanism of arsenic toxicity on human lymphocytes, we use accelerated cytotoxicity mechanisms screening (ACMS) technique. Lymphocytes were isolated from blood of healthy persons using Ficoll-paque PLUS standard method. Following treatment of human lymphocytes with 0.05-50 μM of arsenic for 12 h, cell viability was measured. For determination of mechanistic parameters, isolated human lymphocytes incubated with 1/2IC5012h (7.5 μM), IC5012h (15 μM) and 2IC5012h (30...
Regulation of Arsenic Trioxide-induced Cellular Responses by Mnk1 and Mnk2
Journal of Biological Chemistry, 2008
Arsenic trioxide (As 2 O 3) is a potent inducer of apoptosis of malignant cells in vitro and in vivo, but the precise mechanisms by which it mediates such effects are not well defined. We provide evidence that As 2 O 3 induces phosphorylation/ activation of the MAPK signal-integrating kinases (Mnks) 1 and 2 in leukemia cell lines. Such activation is defective in cells with targeted disruption of the p38␣ MAPK gene, indicating that it requires upstream engagement of the p38 MAPK pathway. Studies using Mnk1 ؊/؊ or Mnk2 ؊/؊ , or double Mnk1 ؊/؊ Mnk2 ؊/؊ knockout cells, establish that activation of Mnk1 and Mnk2 by arsenic trioxide regulates downstream phosphorylation of the eukaryotic initiation factor 4E at Ser-209. Importantly, arsenic-induced apoptosis is enhanced in cells with targeted disruption of the Mnk1 and/or Mnk2 genes, suggesting that these kinases are activated in a negative-feedback regulatory manner, to control generation of arsenic trioxide responses. Consistent with this, pharmacological inhibition of Mnk activity enhances the suppressive effects of arsenic trioxide on primary leukemic progenitors from patients with acute leukemias. Taken together, these findings indicate an important role for Mnk kinases, acting as negative regulators for signals that control generation of arsenic trioxide-dependent apoptosis and antileukemic responses.
Arsenic-Induced Carcinogenesis and Immune Dysregulation
International Journal of Environmental Research and Public Health, 2019
Arsenic, a metal ubiquitously distributed in the environment, remains an important global health threat. Drinking arsenic-contaminated water is the major route of human exposure. Exposure to arsenic contributes to several malignancies, in the integumentary, respiratory, hepatobiliary, and urinary systems. Cutaneous lesions are important manifestations after long-term arsenic exposure. Arsenical skin cancers usually herald the development of other internal cancers, making the arsenic-induced skin carcinogenesis a good model to investigate the progression of chemical carcinogenesis. In fact, only a portion of arsenic-exposed humans eventually develop malignancies, likely attributed to the arsenic-impaired immunity in susceptible individuals. Currently, the exact pathophysiology of arsenic-induced carcinogenesis remains elusive, although increased reactive oxidative species, aberrant immune regulations, and chromosome abnormalities with uncontrolled cell growth might be involved. This ...
Journal of Biological Chemistry, 2002
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 ␣ and  isoforms of the p38 mitogenactivated 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 (p38AGF) 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. Arsenic trioxide (As 2 O 3) suppresses the growth of malignant cells in vitro and in vivo (1-4). Several studies have shown that this agent exhibits potent growth inhibitory effects on several cell lines of diverse malignant phenotypes, including leukemia, multiple myeloma, prostate carcinoma, and neuroblastoma
The FASEB Journal, 2002
Chronic exposures to inorganic arsenic (iAs) have been linked to increased incidences of various cancers, including cancer of the urinary bladder. Mechanisms by which iAs promotes cancer may include stimulation of activator protein-1 (AP-1) DNA binding through increased expression and/or phosphorylation of the AP-1 constituents. However, the role of methylated metabolites of iAs in AP-1 activation has not been thoroughly examined. In this study, we show that short-time exposures to 0.1-5 µM arsenite (iAs III) or the methylated trivalent arsenicals methylarsine oxide (MAs III O), or iododimethylarsine (DMAs III I) induce phosphorylation of c-Jun and increase AP-1 DNA binding activity in human bladder epithelial cells. DMAs III I and especially MAs III O are considerably more potent than iAs III as inducers of c-Jun phosphorylation and AP-1 activation. Phosphorylated c-Jun, JunB, JunD, and Fra-1, but not c-Fos, FosB, or ATF-2, are detected in the AP-1-DNA binding complex in cells exposed to trivalent arsenicals. In cells transiently transfected with an AP-1-dependent promoter-reporter construct, MAs III O was more potent than iAs III in inducing the AP-1-dependent gene transcription. Exposures to trivalent arsenicals induce phosphorylation of extracellular signal-regulated kinase (ERK), but not c-Jun N-terminal kinases or p38 kinases. These results indicate that an ERK-dependent signal transduction pathway is at least partially responsible for c-Jun phosphorylation and AP-1 activation in UROtsa cells exposed to inorganic or methylated trivalent arsenicals.