LXR agonist regulates the carcinogenesis of PCa via the SOCS3 pathway.
BACKGROUND
Down-regulation of suppressor of cytokine signaling 3 (SOCS3) inhibits prostate cancer (PCa) cell growth. Liver X receptors (LXRs) agonists have been recently introduced for PCa treatment. We postulated that LXR may inhibit the carcinogenesis of PCa via the SOCS3 pathway.


METHODS
LNCaP cells were cultured and transfected with SOCS3 small-interfering RNA (SOCS3-siRNA) and control small-interfering RNA (control-siRNA). Then cells were treated with LXR activator (GW3965). The expressions of PCa related transcript factors, e.g. transcription 3 (STAT3), nuclear factor kappa B (NF-κB) and activation protein 1(AP1) were detected by western blot assay. In vitro cell proliferation, cell migration, cell invasion and apoptosis were analysed. Nude mice were used for in vivo tumorgenesis.


RESULTS
In cells treated with control-siRNA, GW3965 enhanced SOCS3 expression and significantly inhibited the phosphorylation of STAT3, NF-κB and AP1 expressions, accompanied by dramatically reduced cellular proliferation rate, immigration and invasion of cultured cells. In cells treated with SOCS3-siRNA, the inhibitory effects of LXR activator on the phosphorylation of STAT3 and expressions of NF-κB and AP1 were totally abolished. The cell proliferation rate, immigration and invasion were markedly elevated by SOCS3 gene mutation, even with GW3965 treatment. The in vivo tumorgenesis assay showed that GW3965 significantly reduced the tumor volumes in tumor-bearing nude mice receiving saline injection, but failed to limit the tumor volume in tumor-bearing nude mice receiving SOCS3 antibody injection.


CONCLUSIONS
Our results provide evidence in support of the notion that LXR agonist may regulate the carcinogenesis of PCa via the SOCS3 pathway.
Department of Urology, Southwest Hospital, Third Military Medical University, Chongqing, China.
Weihua
W
Fu
Jiwei
J
Yao
Yan
Y
Huang
Qianwei
Q
Li
Weibing
W
Li
Zhiwen
Z
Chen
Fengtian
F
He
Zhansong
Z
Zhou
Junan
J
Yan
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D015153:Blotting, Western; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D008819:Mice, Nude; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D011471:Prostatic Neoplasms / Q000473:pathology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014162:Transfection
D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins