NSAID-activated gene 1 mediates pro-inflammatory signaling activation and paclitaxel chemoresistance in type I human epithelial ovarian cancer stem-like cells

// Ki-Hyung Kim 1, 2, 3, * , Seong-Hwan Park 1, 5, * , Kee Hun Do 1, 5, * , Juil Kim 1, 5 , Kyung Un Choi 2, 4 , Yuseok Moon 1, 2, 5 1 Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan, South Korea 2 Biomedical Research Institute and Pusan Cancer Center, Pusan National University Hospital, Busan, South Korea 3 Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Busan, South Korea 4 Department of Pathology, Pusan National University School of Medicine, Busan, South Korea 5 Research Institute for Basic Sciences, Pusan National University, Busan, South Korea * Ki-Hyung Kim, Kee Hun Do and Seong-Hwan Park equally contributed to the present study Correspondence to: Yuseok Moon, email: moon@pnu.edu Keywords: NAG-1, epithelial ovary cancer, paclitaxel, NF-κB, chemoresistance Received: February 24, 2016     Accepted: September 20, 2016     Published: September 30, 2016 ABSTRACT Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in developed countries. Chronic endogenous sterile pro-inflammatory responses are strongly linked to EOC progression and chemoresistance to anti-cancer therapeutics. In the present study, the activity of epithelial NF-κB, a key pro-inflammatory transcription factor, was enhanced with the progress of EOC. This result was mechanistically linked with an increased expression of NSAID-Activated Gene 1 (NAG-1) in MyD88-positive type I EOC stem-like cells, compared with that in MyD88-negative type II EOC cells. Elevated NAG-1 as a potent biomarker of poor prognosis in the ovarian cancer was positively associated with the levels of NF-κB activation, chemokines and stemness markers in type I EOC cells. In terms of signal transduction, NAG-1-activated SMAD-linked and non-canonical TGFβ-activated kinase 1 (TAK-1)-activated pathways contributed to NF-κB activation and the subsequent induction of some chemokines and cancer stemness markers. In addition to effects on NF-κB-dependent gene regulation, NAG-1 was involved in expression of EGF receptor and subsequent activation of EGF receptor-linked signaling. The present study also provided evidences for links between NAG-1-linked signaling and chemoresistance in ovarian cancer cells. NAG-1 and pro-inflammatory NF-κB were positively associated with resistance to paclitaxel in MyD88-positive type I EOC cells. Mechanistically, this chemoresistance occurred due to enhanced activation of the SMAD-4- and non-SMAD-TAK-1-linked pathways. All of the present data suggested NAG-1 protein as a crucial mediator of EOC progression and resistance to the standard first-line chemotherapy against EOC, particularly in MyD88-positive ovarian cancer stem-like cells.