Inhibition of the Signal Transducers and Activators of Transcription (STAT) 3 Signalling Pathway by AG490 in Laryngeal Carcinoma Cells

Abstract

Signal transducers and activators of transcription (STAT) are important in the development of laryngeal carcinomas and are potential novel molecular targets for therapy to improve survival of patients with this cancer. This study was designed to investigate the influence of the janus activated kinase (JAK)/STAT inhibitor AG490 on proliferation and apoptosis of Hep-2 human laryngeal cancer cells and whether there was any inhibition by AG490 of the JAK/STAT3 signalling pathway. AG490 inhibited cell proliferation in dose- and time-dependent manners and induced apoptosis in Hep-2 cells, with the number of apoptotic cells increasing with time. AG490 inhibited G1 to S cell cycle transition and induced G1 cell cycle arrest as well as significantly down-regulating STAT3, phosphorylated STAT3 and survivin in Hep-2 cells. This study showed that AG490 significantly inhibited proliferation and induced apoptosis of laryngeal carcinoma cells through down-regulation of STAT3 and survivin, suggesting a potential target for laryngeal carcinoma treatment.

Effects of AG490 and S3I-201 on regulation of the JAK/STAT3 signaling pathway in relation to angiogenesis in TRAIL-resistant prostate cancer cells in vitro

“…In healthy human and animal cells, ligand-dependent activation of STATs is a transient process, lasting for several minutes to several hours. By contrast, the results of the current study are consistent with those of a previous study by Zhang et al (19). Treatment of hepatoma cell lines with NSC 74859 resulted in the downregulation of p-STAT3 levels, whereas no change was identified in the levels of total STAT3 (46).…”

“…Therefore, it has become a focus of interest as a new target for cancer therapy similar to that of the JAK proteins (14,15). Previously, activated STAT3 has been shown to promote cell proliferation, metastasis and angiogenesis and to protect tumor cells from apoptosis by regulating associated genes, including Bcl-xL, Bcl-2, Fas, cyclin D1, c-myc, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2/-9, myeloid cell leukemia sequence 1 (MCL-1) and survivin (16–19). Abnormalities in the JAK/STAT3 pathway are critical in the oncogenesis of several types of cancer (20) and are involved in the survival, proliferation and metastases of CaP (21–23).…”

Down-regulation of SOX18 inhibits laryngeal carcinoma cell proliferation, migration, and invasion through JAK2/STAT3 signaling

“…To further explore the possible mechanism by which SOX18 regulated cell functions in laryngeal cancer, the effect of SOX18 on JAK2/STAT3 signaling was examined. JAK2/STAT3 signal pathway exists in various types of cancers including laryngeal cancer [22,23], which is correlated with cell proliferation, apoptosis, and differentiation [24,25]. In our study, the results indicated that down-regulation of SOX18 significantly suppressed the expressions of JAK-STAT3 upstream effectors (PDGF and IGF1R) and the phosphorylation of JAK2 and STAT3, while overexpression of SOX18 exerted the contrary effect.…”

Identification of laryngeal cancer prognostic biomarkers using an inflammatory gene-related, competitive endogenous RNA network

“…IceNet mRNAs were enriched in 122 GO terms (false discovery rate (FDR) <0.05) mainly in seven functional clusters, including biosynthetic process, cell communication, cell cycle, cell death and apoptosis, cell proliferation, protein localization process, and RNA splicing (Figure 1E), along with 50 KEGG pathways (P<0.05), including cancer, focal adhesion, and several signaling pathways (Figure 1F, Supplementary Table 2). All enriched signaling pathways, including MAPK, NOD-like receptor, Jak-STAT and p53 signaling, are known contributors to LC pathogenesis [13–16]. …”