IL-6 promotes nuclear translocation of HIF-1α to aggravate chemoresistance of ovarian cancer cells

The inflammatory milieu in tumor modulates the resistance to the conventional antitumoral therapies. Interleukin-6 (IL-6), a pleiotropic pro-inflammatory cytokine and a crucial mediator of tumor development, has been targeted as a therapeutic strategy to overcome chemoresistance in the treatment of tumors. The protein levels and nuclear translocation of HIFs (hypoxia-inducible factors), such as HIF-1 alpha, are linked to the drug resistance of tumor cells. However, whether IL-6 promotes the nuclear translocation of HIF-1 alpha and the related mechanism remain to be investigated. We applied two ovarian cancer (OvCa) cell lines, A2780 cells and SKOV3 cells for the in vivo and in vitro studies. We found that IL-6 up-regulates the HIF-1 alpha expression via the signal transducer and activator of transcription 3 (STAT3) signaling under hypoxia in either endogenous or exogenous way, and then we proved that IL-6 enhances the transcriptional activity of HIF-1 alpha via the STAT3 signaling. Further mechanism research revealed that IL-6 promotes the nuclear translocation of HIF-1 alpha through the STAT3 signaling under hypoxia. Proliferation assay and apoptosis assay were applied and proved that IL-6 enhances the chemoresistance of OvCa cells against cisplatin through the upregulation of HIF-1 alpha via the STAT3 signaling in vitro. The In vivo studies confirmed the effect of IL-6 in increasing the chemoresistance of OvCa cells against cisplatin through the IL-6/STAT3/HIF-1 alpha loop in the animal models. Our data elucidates the explicit mechanism of IL-6/STAT3/HIF-1 alpha loop in OvCa and also provides new insights into the development of different approaches for the inflammation-induced and hypoxia-induced resistance in tumor therapies.

Automated summary

IL-6 enhances the chemoresistance of ovarian cancer cells against cisplatin by facilitating the nuclear translocation of HIF-1 alpha via the STAT3 signaling pathway, both in in vitro and in vivo studies.