Role of TLR4 for paclitaxel chemotherapy in human epithelial ovarian cancer cells
Article first published online: 20 JAN 2009
© 2009 The Authors. Journal Compilation © 2009 Stichting European Society for Clinical Investigation Journal Foundation
European Journal of Clinical Investigation
Volume 39, Issue 2, pages 157–164, February 2009
How to Cite
Wang, A. C., Su, Q. B., Wu, F. X., Zhang, X. L. and Liu, P. S. (2009), Role of TLR4 for paclitaxel chemotherapy in human epithelial ovarian cancer cells. European Journal of Clinical Investigation, 39: 157–164. doi: 10.1111/j.1365-2362.2008.02070.x
- Issue published online: 20 JAN 2009
- Article first published online: 20 JAN 2009
- Received 9 August 2008; accepted 7 November 2008
- ovarian cancer;
Background Paclitaxel has been reported to be a ligand to Toll like receptor 4 (TLR4). Myeloid differentiation factor 88(MyD88) was described as a myeloid differentiation primary response gene. TLR4 signalling owns two pathways: MyD88-dependent and MyD88-independent pathways. XIAP is a key member of the inhibitor of apoptosis protein family. Akt is a major downstream target of growth factor receptor tyrosine kinases, which negatively regulates apoptotic pathways through phosphorylation (pAkt). The aim of the present study is to investigate the role of TLR4 in paclitaxel resistance of ovarian cancer cells.
Materials and methods We reconstructed the RNA interference expression vector, pGenesil-1-U6 specifically targeting TLR4 mRNA, which was stable transfected into the human ovarian cancer cell line SKOV3 (MyD88-positive expression) and A2780 (MyD88-negative expression). Cell proliferation, cell cycle distribution and cell apoptosis were assessed in the cells transfected with scramble control shRNA (SKOV3/shControl, A2780/shControl) and TLR4 shRNA (SKOV3/shTLR4, A2780/shTLR4) to explore the possible functions of TLR4 in ovarian cancer cells growth. The expression of TLR4, MyD88, XIAP, Akt and pAkt was analysed by Western blot analysis.
Results A knockdown of TLR4 levels down-regulated the expression of XIAP and pAkt. And it restored the inhibitory effect of paclitaxel on cell proliferation and impeding cell cycle progression in SKOV3 cells.
Conclusions It suggests that TLR4 negatively regulates paclitaxel chemotherapy and MyD88 is an essential downstream factor to TLR4 signalling for this resistance. Knockdown of TLR4 induces paclitaxel chemosensitivity which might depress the Akt pathway. The TLR4-MyD88 signalling represents an important source to promote tumour growth.