Arsenic inhibition of the JAK-STAT pathway

Abstract

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is an essential cascade for mediating normal functions of different cytokines in the development of the hematopoietic and immune systems. Chronic exposure to arsenic has been found to cause immunotoxicity and has been associated with the suppression of hematopoiesis (anemia and leukopenia). Here, we report the novel finding of arsenic-mediated inactivation of the JAK-STAT signaling pathway by its direct interaction with JAK tyrosine kinase. Pretreatment with sodium arsenite strongly inhibited IL-6-inducible STAT3 tyrosine phosphorylation in HepG2 cells and did not affect its serine phosphorylation. As a result, sodium arsenite completely abolished STAT activity-dependent expression of suppressors of cytokine signaling (SOCS). Both cellular and subcelluar experiments showed that the inhibition of JAK-STAT signaling resulted from JAK tyrosine kinase's direct interaction with arsenite, and that arsenic's suppression of JAK tyrosine kinase activity also occurred in the interferon c (IFNc) pathway. The ligandindependent inhibition by arsenic indicates that JAK was the direct target of arsenic action. Other inflammatory stimulants, stress agents, and metal cadmium failed to induce similar effects on the tyrosine phosphorylation of STAT3 as arsenic does. Our experiments also revealed that arsenic inactivation of the JAK-STAT pathway occurred independent of arsenic activation of MAP kinases. Taken together, our findings indicate that arsenic directly inhibits JAK tyrosine kinase activity and suggest that this direct interference in the JAK-STAT pathway may play a role in arsenic-associated pathogenesis.

Arsenic Trioxide Inhibits Hepatitis C Virus RNA Replication through Modulation of the Glutathione Redox System and Oxidative Stress

“…To date, the focus has been on PML and PML-retinoic acid receptor ␣ as major targets of ATO (70). On the other hand, arsenic has been reported to modulate other cell-signaling pathways, especially stress-responsive transcription factors, such as nuclear factor B (NF-B), activator protein 1 (AP-1), and STAT3 (12,37,38,62). Therefore, we examined the involvement of several stress-responsive pathways in the anti-HCV activity of ATO by luciferase-based reporter assays or Western blot analysis using an antibody which specifically recognizes STAT3 phosphorylated at tyrosine 705.…”

“…5C and D), suggesting that the AP-1 pathway is also not involved in the anti-HCV activity of ATO. Regarding the STAT3 signaling pathway, ATO has been reported to inhibit the phosphorylation of the STAT3 tyrosine at 705, leading to inactivation of the JAK-STAT signaling pathway (12,62). In contrast, it has been reported that HCV constitutively phosphorylates and activates STAT3 (49,59,67).…”

“…In fact, oxidative stress has been shown to trigger STAT3 tyrosine phosphorylation and nuclear translocation, which correlate with the activation of STAT3, leading to its DNA-binding activity (9). In contrast, ATO inhibited the STAT3 tyrosine phosphorylation through direct interaction with JAK kinase, thereby suppressing the transcriptional activity of STAT3 (12,62). Importantly, STAT3 activation has been reported to be associated with HCV RNA replication (59, 69).…”

Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

“…At higher doses of arsenite (>10 μM), strong necrosis starts to substitute apoptosis of cancer cells, diminishing usefulness of this treatment. Two critical enzyme targets, which are suppressed by arsenite treatment, are IKKβ [41] and JAK2 [58]. Inhibition of these enzymes results in a suppression of the NF-κB and STAT3-mediated signaling, which downregulates gene expression of cFLIP, XIAP, cIAP, BclxL [2,59], proteins involved in the regulation of anti-apoptotic protection in the cell (Fig.…”

Gender-Specific Protective Effect of Hemoglobin on Arsenic-Induced Skin Lesions

“…A small epidemiologic study among a Mexican population exposed to arsenic-contaminated drinking water observed that chronic arsenic exposure increased certain enzyme activity in the heme biosynthesis pathway, although the biological significance of this alteration is not known (14). Arsenite can inactive the Janus-activated kinase/signal transducers and activators of transcription pathway, which plays a critical role in the function of hematopoietic cells, cell proliferation, and differentiation (43). Arsenic-contaminated drinking water has been associated with increased microvascular disease (44) and deficits of capillary blood flow and permeability in clinically normal skin of patients with chronic arsenical poisoning (45).…”