YC-1 suppresses constitutive nuclear factor-kappaB activation and induces apoptosis in human prostate cancer cells.
Although the indazole compound, YC-1, is reported to exert anticancer activities in several cancer cell types, its target and mechanism of action have not been well explored. The objectives of this study were to ascertain whether YC-1 directly induces apoptosis in prostate cancer cells and to explore the mechanism(s) whereby YC-1 causes cell death. Hormone-refractory metastatic human prostate cancer PC-3 cells were selected for this study. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay indicated that YC-1 suppresses growth of PC-3 cells in a concentration-dependent and time-dependent manner. Apoptosis was determined using 4',6-diamidino-2-phenylindole staining, and cell cycle progression was examined by FACScan flow cytometry. YC-1 treatment showed chromatin condensation and increased the percentage of PC-3 cells in the hypodiploid sub-G0-G1 phase, indicative of apoptosis. Additionally, exposure to YC-1 was found to induce activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Translocation and activation of nuclear factor-kappaB (NF-kappaB) were determined by immunofluorescent staining and ELISA, respectively. The results showed that YC-1 abolished constitutive nuclear translocation and activation of NF-kappaB/p65. Furthermore, inhibition of inhibitor of kappaBalpha (IkappaBalpha) phosphorylation and accumulation of IkappaBalpha were observed. The antitumor effects of YC-1 were evaluated by measuring the growth of tumor xenografts in YC-1-treated severe combined immunodeficient mice. The volumes of PC-3 tumors produced in severe combined immunodeficient mice were observed to decline significantly after treatment with YC-1 compared with vehicle controls. We concluded that the antitumor effects of YC-1 in PC-3 cells include the induction of apoptosis and the suppression of NF-kappaB activation. Given these unique actions, further investigations of the effects of YC-1 against hormone-refractory prostate cancer are warranted.
Huang
Yao-Ting
YT
Pharmacological Institute, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Taipei 100, Taiwan. cmteng@ntumc.org.
Pan
Shiow-Lin
SL
Guh
Jih-Hwa
JH
Chang
Ya-Ling
YL
Lee
Fang-Yu
FY
Kuo
Sheng-Chu
SC
Teng
Che-Ming
CM
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007191:Indazoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051996:Transcription Factor RelA / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D061945:Caspase Inhibitors; D020672:I-kappa B Proteins; D007191:Indazoles; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases