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.
Highlights
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy and one of the leading causes of cancer-related mortality among women in developed countries [1,2,3]
Evidence was demonstrated for the involvement of non-steroidal anti-inflammatory drugs (NSAIDs)-Activated Gene 1 (NAG-1) in pro-inflammatory activation, cancer stemness, and chemoresistance in human type 1 EOC cells
NAG-1 mediated nuclear factor-κB (NF-κB) activation through the SMAD4 or TGFβ-activated kinase 1 (TAK-1)-linked signaling pathways, which was critical for EOC drug resistance
Summary
Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy and one of the leading causes of cancer-related mortality among women in developed countries [1,2,3]. Prolonged NF-κB activation and the subsequent production of pro-inflammatory chemokines in myeloid differentiation protein 88 (MyD88)-expressing epithelial ovarian cancer cells are involved in chemoresistance to paclitaxel, a crucial drug for standard first-line chemotherapy [24, 25]. Based on their chemo-response, EOC cells are classified into 2 groups: chemoresistant (type I) and chemosensitive (type II) [26, 27]. Inhibition of inflammation prevents tumor repair and renewal of EOC stem cells and may have a significant effect on disease recurrence
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.