Small interfering RNA-directed targeting of Toll-like receptor 4 inhibits human prostate cancer cell invasion, survival, and tumorigenicity.
A major cause of tumor treatment failure is cancer cell metastasis. Toll-like receptor 4 (TLR4)-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. In this study, we investigated the biological roles of TLR4 in prostate metastatic cell invasion and survival, and the potential of gene silencing of TLR4 using small interfering RNA (siRNA) for treatment of cancer. In cultured human prostate cancer cell lines, TLR4 were higher PC3 and DU145 as compared with the poorly metastatic LNCaP indicating that up-regulation of TLR4 was positively correlated with metastasis of tumor cell. In the highly metastatic cancer cell PC3, gene silencing of TLR4 using siRNA significantly inhibited TLR4 mRNA expression and protein level. Knockdown of TLR4 in PC3 cells resulted in a dramatic reduction of tumor cell migration and invasion as indicated by a Matrigel invasion assay. Furthermore, TLR4 siRNA suppressed cell viability and ultimately caused the induction of apoptotic cell death. The effects were associated with abrogating TLR4-mediated signaling to downstream target molecules such as myeloid differentiation factor 88 (MyD88), adaptor-inducing IFN-beta (TRIF), and interferon regulatory factor-1 (IRF-1). In a mouse prostate cancer model, administration with the plasmid construct expressing siRNA for TLR4 obviously inhibited established tumor growth and survival. These studies revealed evidence of a multifaceted signaling network operating downstream of TLR4-mediated tumor cell invasion, proliferation, and survival. Thus, RNA interference-directed targeting of TLR4 may raise the potential of its application for cancer therapy.
Hua
Dong
D
Wuxi Fourthly People's Hospital, Soochow University, Wuxi, Jiangsu, PR China.
Liu
Meng-Yuan
MY
Cheng
Zhi-de
ZD
Qin
Xiang-Jing
XJ
Zhang
Hai-Mou
HM
Chen
Yong
Y
Qin
Gang-Jian
GJ
Liang
Gang
G
Li
Ji-Nan
JN
Han
Xiao-Feng
XF
Liu
Dong-Xu
DX
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D033942:Adaptor Proteins, Vesicular Transport; D050856:Interferon Regulatory Factor-1; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4