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

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.

Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

“…In MyD88-positive type I epithelial ovarian cancer cells, GDF-15 induced NF-κB signaling in vitro, thereby up-regulating stemness markers (OCT-4, SOX-2) and chemokine expression (CXCL-1, IL-8, and MCP-1) (166). In other studies on ovarian cancer cells, GDF-15 was found to signal via PI3K/mTOR, MAP kinases, phosphorylation of p38, Akt, and 4EBP1 to promote proliferation, anchorage-independent growth, invasion and upregulation of matrix metalloproteinases MMP2/9 and vascular endothelial growth factor (VEGF) (167).…”

“…It provides a niche for tumor cells, protecting them against immunosurveillance and enabling them to retain a dedifferentiated, stem cell-like state. The various reports on GDF-15 promoting stemness in cancer cells (96,165,166,171) might thus be explained by GDF-15 shaping the tumor microenvironment. Moreover, the diagnostically most essential cells in the tumor microenvironment are immune cells.…”

GDF15 promotes glioma stem cell-like phenotype via regulation of ERK1/2–c-Fos–LIF signaling

“…In glioma, GDF15 is involved in regulating cell proliferation and immune escape 16 ; moreover, it has been correlated with poor patient prognosis and considered an oncogenic factor 17 . In solid tumors, GDF15 promotes the self-renewal capacity of cancer stem cells in gastric 18 , breast 19 , liver 20 , and ovarian cancers 21 . However, the function of GDF15 in GSCs remains to be elucidated.…”

Enterocyte-Based Bioassay via Quantitative Combination of Proinflammatory Sentinels Specific to 8-keto-trichothecenes

“…Based on our previous report ( 41 ), formalin-fixed paraffin-embedded tissues were cut, deparaffinized, and rehydrated. The tissue sections were heated in 10 mM sodium acetate (pH 9.0) for 5 min at 121°C for antigen retrieval.…”

“…Based on our previous reports ( 40 , 41 ), RNA was extracted using RiboEx (GeneAll Biotech, Seoul, South Korea) according to the manufacturer's instructions. RNA (3 μg) from each sample was transcribed to cDNA using Prime RT premix (Genetbio, Nonsan, South Korea).…”