title: Cisplatin treatment increases stemness through upregulation of hypoxia-inducible factors by interleukin-6 in non-small cell lung cancer.
abstract: Cisplatin-resistant A549 and H157 (A549CisR and H157CisR) non-small cell lung cancer cells show increased stemness of cancer stem cells (CSCs) compared to their parental cells. We investigated whether interleukin-6 (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, whereas IL-6 treatment of parental cells resulted in increased cisplatin resistance. Expression of the CSC markers was significantly upregulated in IL-6-expressing scramble cells (in vitro) and scramble cell-derived tumor tissues (in vivo) after cisplatin treatment, but not in IL-6 knocked down (IL-6si) (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 upregulated by IL-6 and responsible for the increased CSC stemness on cisplatin treatment. Mechanism dissection studies found that upregulation of HIFs by IL-6 was through transcriptional control and inhibition of HIF degradation. Treatment of HIF inhibitor (FM19G11) abolished the upregulation of CSC markers and increased sphere formations in IL-6 expressing cells on cisplatin treatment. In all, IL-6-mediated HIF upregulation 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.
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.|Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.|Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Shanzhou
authors.initials: S
authors.lastname: Duan
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Tsai
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Keng
authors.affiliation: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Yongbing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Yuhchyau
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051793:Hypoxia-Inducible Factor 1; D015850:Interleukin-6; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin
keywords: Cancer stem cell; cisplatin-resistance; hypoxia-inducible factor; interleukin-6; non-small cell lung cancer