TLR4 activates NF-?B in human ovarian granulosa tumor cells.

ABSTRACT: Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-?B) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to I?B degradation and activation of NF-?B. NF-?B activation was confirmed by nuclear localization of NF-?B p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-?B signaling attenuated LPS-induced TNF? plus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-?B signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-?B does not sensitize GCTs to TRAIL or cisplatin.

SUBMITTER: Woods DC 

PROVIDER: S-EPMC3118942 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature