TLR4 induces tumor growth and inhibits paclitaxel activity in MyD88-positive human ovarian carcinoma in vitro

In ovarian cancer patients, chemotherapy resistance is the principal factor restricting long-term treatment. Paclitaxel (Pac) has been previously reported to be a ligand to Toll-like receptor 4 (TLR4). It was determined that TLR4 signaling is divided into the following two pathways: Myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent. The present study investigated the effect of TLR4 ligation by Pac in MyD88-positive (MyD88+) and MyD88-negative (MyD88-) human ovarian cancer cell lines. An RNA interference expression vector was specifically constructed to target TLR4 mRNA, which was stably transfected into the human ovarian cancer cell lines (SKOV3, OVCAR3, A2780 and 3AO). Cytokines, including interleukin (IL)-6 and IL-8, were detected. Cell proliferation and apoptosis were assessed in the cells transfected with scramble control and TLR4 shRNA to explore the possible functions of TLR4 in ovarian cancer cell growth. It was found that lipopolysaccharide and Pac significantly increase the secretion of IL-6 and IL-8 in the SKOV3 cell line. Similarly, Pac resulted in a significant upregulation of IL-6 and IL-8 in OVCAR3 cells, but not in A2780 and 3AO cells. These results suggested that in MyD88+ ovarian cancer cell lines, TLR4 depletion shows increased sensitivity to Pac treatment in inhibiting cell proliferation compared with in cells without TLR4 knockdown. On the contrary, such changes were not found in MyD88- cells (A2780 and 3AO). TLR4 negatively regulates Pac chemotherapy, particularly in terms of cell proliferation, and TLR4 may be a novel treatment target in Pac-resistant ovarian cancer.