Cisplatin treatment increases stemness via up-regulation of hypoxia inducible factors by IL-6 in non-small cell lung cancer

Summary

Cisplatin-resistant A549 and H157 (A549CisR and H157CisR) non-small cell lung cancer (NSCLC) cells exhibited increased stemness of cancer stem cells (CSCs) compared to their parental cells. We investigated whether IL-6 signaling contributes to this increased stemness in cisplatin-resistant cells. When A549CisR and H157CisR cells were treated with neutralizing IL-6 antibody, decreased cisplatin-resistance was observed while IL-6 treatment of parental cells resulted in increased cisplatin-resistance. Expression of the CSC markers was significantly up-regulated in IL-6 expressing sc cells (in vitro) and sc cell-derived tumor tissues (in vivo) upon cisplatin treatment, but not in IL-6 (in vitro) cells and in IL-6si cell-derived tumor tissues (in vivo), suggesting the importance of IL-6 signaling in triggering increased stemness during cisplatin-resistance development. Hypoxia inducible factors (HIFs) were up-regulated by IL-6 and responsible for the increased CSC stemness upon cisplatin treatment. Mechanism dissection studies found that up-regulation of HIFs by IL-6 was via transcriptional control and through inhibition of HIFs degradation. Treatment of HIF inhibitor (FM19G11) abolished the up-regulation of CSC markers and increased sphere formations in IL-6 expressing cells upon cisplatin treatment. In all, IL-6 mediated-HIF up-regulation is important in increasing stemness during cisplatin-resistance development, and we suggest that the strategies of inhibiting IL-6 signaling or its downstream HIF molecules can be used as future therapeutic approaches to target CSCs after cisplatin treatment for lung cancer.

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