Opposing Effects of Chelidonine on Tyrosine and Serine Phosphorylation of STAT3 in Human Uveal Melanoma Cells.

István Csomós,Csenge Filep,István Rebenku,Andrea Bodnár,György Vámosi,László Mátyus,Tamás Kovács,Péter Nagy,Enikő Nizsalóczki

doi:10.3390/ijms222312974

István Csomós, Csenge Filep + Show 7 more

Open Access

https://doi.org/10.3390/ijms222312974

Copy DOI

Abstract

STAT3 is a transcription factor that regulates various cellular processes with oncogenic potential, thereby promoting tumorigenesis when activated uncontrolled. STAT3 activation is mediated by its tyrosine phosphorylation, triggering dimerization and nuclear translocation. STAT3 also contains a serine phosphorylation site, with a postulated regulatory role in STAT3 activation and G2/M transition. Interleukin-6, a major activator of STAT3, is present in elevated concentrations in uveal melanomas, suggesting contribution of dysregulated STAT3 activation to their pathogenesis. Here, we studied the impact of chelidonine on STAT3 signaling in human uveal melanoma cells. Chelidonine, an alkaloid isolated from Chelidonium majus, disrupts microtubules, causes mitotic arrest and provokes cell death in numerous tumor cells. According to our flow cytometry and confocal microscopy data, chelidonine abrogated IL-6-induced activation and nuclear translocation, but amplified constitutive serine phosphorylation of STAT3. Both effects were restricted to a fraction of cells only, in an all-or-none fashion. A partial overlap could be observed between the affected subpopulations; however, no direct connection could be proven. This study is the first proof on a cell-by-cell basis for the opposing effects of a microtubule-targeting agent on the two types of STAT3 phosphorylation.

Highlights

Signal transducer and activator of transcription-3 (STAT3) belongs to the family of latent transcription factors that reside predominantly in the cytoplasm of resting cells.Activation of STAT3 requires phosphorylation on the tyrosine 705 residue, which is followed by its dimerization and nuclear translocation
Our results demonstrated the involvement of STAT3 signaling in the mechanism action of our chelidonine in human uveal melanoma cells,ofwhich raises the ap-in
To investigate the potential of chelidonine on the cells activation of STAT3, OCM-1impact and OCM-3 uveal melanoma were cultured for phosphorylation) of STAT3, OCM-1 and OCM-3 uveal melanoma cells were cultured for 24 h in the presence of chelidonine or dimethyl sulfoxide (DMSO) alone and stimulated

Summary

Introduction

Signal transducer and activator of transcription-3 (STAT3) belongs to the family of latent transcription factors that reside predominantly in the cytoplasm of resting cells. Activation of STAT3 requires phosphorylation on the tyrosine 705 residue, which is followed by its dimerization and nuclear translocation. STAT3 in the nucleus initiates the transcription of a vast range of genes playing a pivotal role in various biological processes with oncogenic potential (e.g., cell proliferation, anti-apoptotic processes, cell migration, etc.). Uncontrolled (prolonged or constitutive) activation of STAT3 may lead to dysregulation of target gene expression, thereby promoting malignant transformation and tumor cell survival [1,2,3]. STAT3 is activated by multiple cytokines and growth factors, including the proinflammatory interleukin-6 (IL-6). IL-6 acts through a multimeric receptor complex comprising the cytokine-specific α-chain (IL-6Rα) and the signaling glycoprotein 130 (gp130)

Methods

Results

Conclusion