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

Abstract

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.

TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth

“…The global nature of this interaction is supported by the observation that an oncogenic role for TLR4 in tumor cells has been identified primarily in cancer types known to inactivate TP53 at high frequencies, such as ovarian (24), bladder (25), and head and neck (26) cancers. Further investigation is warranted in other cancer sites to define the association between TLR4 and TP53 and its effect on tumor biology and behavior.…”

Induction of oxidative stress by Taxol® vehicle Cremophor-EL triggers production of interleukin-8 by peripheral blood mononuclear cells through the mechanism not requiring de novo synthesis of mRNA

“…Activating the TLR-4 signaling pathways with paclitaxel was reported to require the presence of MD-2 in the receptor complex, and the difference between human and murine cell response to paclitaxel was attributed to the differences in the MD-2 protein 24, 49 . The engagement of the TLR-4/MD-2 pathway correlated with the development of chemoresistance in cancer cell lines 50, 51 . Activating TLR-4 with paclitaxel resulted in the recruitment of MyD88, induction of anti-apoptotic proteins X-linked inhibitor of apoptosis, Bcl-2, and Bcl-XL, and activation of pro-survival pathways, ultimately leading to increased cancer cell resistance to chemotherapy 52-54 .…”

The inflammatory microenvironment in epithelial ovarian cancer: a role for TLR4 and MyD88 and related proteins

“…LPS ligation to TLR4 results in production of chemokines and cytokines that lead to chemoresistance to paclitaxel by activing the NF-κB pathway in MyD88-positive but not MyD88-negative cells [6]. Moreover, paclitaxel binding to TLR4 can also activate NF-κB pathway and induce chemoresistance only in MyD88-positive cells [7, 20], indicating that co-expression of TLR4 and MyD88 in EOC cells are essential for the activation of TLR4/MyD88/NF-κB signaling pathway.…”