Toll-like receptor 4 ligation confers chemoresistance to docetaxel on PC-3 human prostate cancer cells.
Recent studies have indicated that Toll-like receptors (TLRs) are implicated in the development of chemoresistance in cancer cells. TLR4 has been shown to be highly expressed in prostate cancer cells and contributes to tumor cell survival and invasion. In this study, we aimed to investigate the role of TLR4 signaling in the chemoresistance of prostate cancer cells. We showed that ligation of TLR4 with lipopolysaccharide (LPS) abrogated docetaxel-induced growth suppression in PC-3 prostate cancer cells, with an increase in the half-maximal inhibitory concentration. Downregulation of TLR4 using small-interference RNA sensitized PC-3 cells to docetaxel-induced apoptosis as determined by annexin V staining and poly (ADP-ribose) polymerase cleavage, which was coupled with increased Bax expression and decreased Bcl-2. TLR4 ligation resulted in a marked increase in the phosphorylation of phosphatidylinositol 3-kinase (PI3-K) and Akt. The pretreatment with a PI3-K inhibitor LY294002 reduced LPS-mediated resistance to docetaxel, significantly decreasing the viability of PC-3 cells. Our data show that TLR4 ligation contributes to the chemosensitivity of prostate cancer cells, which at least partially involves the activation of the PI3-K/Akt pathway. Therefore, TLR4 signaling may represent a promising target for the improvement of chemotherapeutic efficacy in prostate cancer.
Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi, China.
Yuntao
Y
Zhang
Yong
Y
Wang
Jianlin
J
Yuan
Weijun
W
Qin
Fei
F
Liu
Fuli
F
Wang
Geng
G
Zhang
Xiaojian
X
Yang
D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D055785:Gene Knockdown Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495345:TLR4 protein, human; D043823:Taxoids; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000077143:Docetaxel; D007770:L-Lactate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt