Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC

Abstract

This study was aimed to elucidate the roles of inhibition of related JAK/STAT pathways in regulating cytotoxicity induced by cisplatin in non-small-cell lung cancer (NSCLC) cell. We treated five non-small-cell lung cancer cell lines with cisplatin alone or with cisplatin and Jak2 inhibitor (ruxolitinib) and assessed cell viability, expression of Jak2 and STAT3 and cell apoptosis. We also investigated the effect of combination treatment inhibited tumor xenograft growth in two human NSCLC xenograft models bearing the cisplatin resistant (H1299) and sensitive (A549) cells. Different cell lines with different genetic background showed half-maximal inhibitory concentrations (IC50) of cisplatin from 4.66 to 68.28 µmol/L. They could be divided into cisplatin intrinsic resistant and cisplatin sensitive cell lines. In cisplatin-resistant cells with higher Jak2 and STAT3 expression, cisplatin and ruxolitinib combination dramatically suppressed the cell growth, down-regulated the expression of phosphorylated STAT3 and induced cleaved caspase-3 expression. Moreover combination with cisplatin and ruxolitinib also significantly inhibited the growth of resistant cell H1299, A549/DDP and H2347 in soft agar model. Finally, combination group significant inhibited the tumor growth and induced the caspase-3 expression compared with either single agent alone (P < 0.05) on the resistant cell xenografts model. The present study indicates that further study is warranted to determine the effectiveness of combination treatment with cisplatin and Jak2/stat3 pathway inhibitor for platinum-resistant NSCLC.

Over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced non-small cell lung cancer cells through PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR

“…The activation of STAT3 protein allows VEGF to promote migration and angiogenesis of vascular endothelial cells. It shows that the STAT3 protein is at the core position in tumor angio- genesis (22). In the present study, we found that over-regulation of microRNA-133b suppressed EGFR, p-JAK2 and p-STAT3 protein expression in cisplatin-induced A549 cells.…”

Periostin Contributes to Cisplatin Resistance in Human Non-Small Cell Lung Cancer A549 Cells via Activation of Stat3 and Akt and Upregulation of Survivin

“…Stat3 signaling is implicated in chemoresistance of NSCLC cells and represents an important therapeutic target for NSCLC [10]. Pharmacological inhibition of the Jak/Stat pathway has been documented to overcome CDDP resistance in NSCLC [26]. Therefore, in this work, we investigated whether activation of Stat3 signaling was linked to periostin-mediated CDDP resistance.…”

Role of the IL-11/STAT3 signaling pathway in human chronic atrophic gastritis and gastric cancer

“…STAT3 is a well-established oncogene that can be constitutively activated in many human cancers including those of the lung, breast, ovary, prostate, colon, and stomach (Burke et al, 2001;Mora et al, 2002;Putoczki et al, 2013;Hu et al, 2014;de Jong et al, 2014). Furthermore, excessive STAT3 activation has been shown to be accompanied by elevated IL-11 expression (Putoczki and Ernst, 2010).…”