sulindac and Carcinoma--Ovarian-Epithelial

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.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents, Phytogenic; Biomarkers, Tumor; Carcinogenesis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Chemokines; Disease Progression; Disease-Free Survival; Drug Resistance, Neoplasm; ErbB Receptors; Female; Fluorescent Antibody Technique; Growth Differentiation Factor 15; Humans; Immunohistochemistry; Inflammation; Kaplan-Meier Estimate; MAP Kinase Kinase Kinases; Microscopy, Confocal; Myeloid Differentiation Factor 88; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Neoplastic Stem Cells; NF-kappa B; Ovarian Neoplasms; Ovary; Paclitaxel; Prognosis; Signal Transduction; Smad4 Protein; Sulindac; Up-Regulation