TLR4 signaling induced by lipopolysacharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer

Toll-like receptors (TLRs) expressed on immune cells trigger inflammatory responses. TLRs are also expressed on ovarian cancer (OvCa) cells, but the consequences of signaling via the TLR4/MyD88 pathway in these cells are unclear. Here, TLR4 and MyD88 expression in OvCa tissues (n=20) and cell lines (OVCAR3, SKOV3, AD10, A2780 and CP70) was evaluated by RT-PCR, Western blots and immunohistochemistry. Cell growth, apoptosis, NF-κB translocation, IRAK4 and TRIF expression and cJun phosphorylation were measured following tumor cell exposure to the TLR4 ligands, lipopolysacharide (LPS) or Paclitaxel (PTX). Culture supernatants were tested for cytokine levels. TLR4 was expressed in all tumors, tumor cell lines and normal epithelium. MyD88 was detectable in tumor tissues and in 3/5 OvCa lines but not in normal cells. In MyD88(+) SCOV3 cells, LPS or PTX binding to TLR4 induced IRAK4 activation and cJun phosphorylation, activated the NF-κB pathway and promoted IL-8, IL-6, VEGF and MCP-1 production and resistance to drug-induced apoptosis. Silencing of TLR4 in SCOV3 cells with siRNA resulted in p-cJun downregulation and a loss of PTX resistance. In PTX sensitive, MyD88(neg) A2780 cells, TLR4 stimulation upregulated TRIF, and TLR4 silencing eliminated this effect. Thus, TLR4/MyD88 signaling supports OvCa progression and chemoresistance, promoting immune escape.