IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and dna repair associated molecules

Abstract

Cisplatin-based chemotherapy is currently the most effective treatment regimen for non-small cell lung cancer (NSCLC), but eventually tumor resistance develops which limits its success. The potential implication of IL-6 signaling in the cisplatin resistance of NSCLC was explored by testing whether NSCLC cells with different levels of intracellular IL-6 show different responses to the cytotoxic treatment of cisplatin. When the cisplatin cytotoxicity of the IL-6 knocked down human NSCLC cells (A549IL-6si and H157IL-6si) were compared with their corresponding scramble control cells (A549sc and H157sc), higher cisplatin cytotoxicity was found in IL-6 si cells than sc cells. Subcutaneous xenograft mouse models were developed using a pair of A549sc and A549IL-6si cells. When the tumor grew to about 400 mm2, mice were treated with cisplatin and tumor regression was monitored. Higher tumor regression was detected in the A549IL-6si xenografts compared to A549sc xenografts following cisplatin treatment. Immunostaining study results from tumor tissues also supported this finding. Expression of anti-apoptotic proteins Bcl-2 and Mcl-1 and DNA repair associated molecules ATM, CHK1, TP73, p53, and ERCC1 were significantly up regulated in cisplatin-treated A549sc and H157sc cells, but no increase was detected in A549IL-6si and H157IL-6si cells. Further inhibitor studies revealed that up regulation of these molecules by IL-6 may be through activation of IL-6 downstream signaling pathways like Akt, MAPK, Stat3, and Erk. These results provide potential for combining cisplatin and inhibitors of IL-6 signaling or its downstream signaling pathway as a future therapeutic approach in preventing development of cisplatin resistant NSCLC tumors.

Cisplatin treatment increases stemness through upregulation of hypoxia‐inducible factors by interleukin‐6 in non‐small cell lung cancer

“…There may be several ways of triggering the IL‐6 effect on influencing cisplatin resistance. Our laboratory has previously shown that IL‐6 increases cisplatin resistance by upregulating molecules related to anti‐apoptosis and DNA repair . We speculate that the IL‐6 effect in increasing CSC stemness is another way of mediating cisplatin resistance in NSCLC.…”

“…We developed two cisplatin‐resistant NSCLC cell lines, A549CisR and H157CisR, by treating parental A549 and H157 cells with an increasing dose of cisplatin over 6 months . These cells showed four to five times higher IC 50 values than parental cells (Fig.…”

“…Interleukin‐6 is detectable in a high percentage of lung cancer patients, and the circulating IL‐6 level has been suggested as a prognostic marker for survival in advanced NSCLC patients treated with chemotherapy . In previous studies, we have shown that the intracellular IL‐6 level is important in developing cisplatin resistance, and this effect was partially through upregulation of the molecules associated with anti‐apoptotic and DNA repair pathways . In this study, we investigated the IL‐6 effect on expanding the CSC population, or stemness, during development of cisplatin resistance, as it has been suggested that cisplatin‐resistant cells enable a higher CSC population and our laboratory and others have found that IL‐6 promotes growth of CSCs …”

“…(9) In previous studies, we have shown that the intracellular IL-6 level is important in developing cisplatin resistance, and this effect was partially through upregulation of the molecules associated with anti-apoptotic and DNA repair pathways. (10) In this study, we investigated the IL-6 effect on expanding the CSC population, or stemness, during development of cisplatin resistance, as it has been suggested that cisplatin-resistant cells enable a higher CSC population (11) and our laboratory and others have found that IL-6 promotes growth of CSCs. (12) Hypoxia-inducible factor is a transcription factor that is responsible for induction of genes associated with cell survival under hypoxia.…”

IL-6 Secreted from Cancer-Associated Fibroblasts Mediates Chemoresistance in NSCLC by Increasing Epithelial-Mesenchymal Transition Signaling

“…25 29 IL-6 and TGF-β-related signaling also induces fibroblast activation in prostate cancer stroma. 30 Crosstalk between IL-6 and TGF-β appears to form vicious cycle that enhances malignant features.…”