title: Cholestane-3β, 5α, 6β-triol suppresses proliferation, migration, and invasion of human prostate cancer cells.
abstract: Oxysterols are oxidation products of cholesterol. Cholestane-3β, 5α, 6β-triol (abbreviated as triol) is one of the most abundant and active oxysterols. Here, we report that triol exhibits anti-cancer activity against human prostate cancer cells. Treatment of cells with triol dose-dependently suppressed proliferation of LNCaP CDXR-3, DU-145, and PC-3 human prostate cancer cells and reduced colony formation in soft agar. Oral administration of triol at 20 mg/kg daily for three weeks significantly retarded the growth of PC-3 xenografts in nude mice. Flow cytometric analysis revealed that triol treatment at 10-40 µM caused G1 cell cycle arrest while the TUNEL assay indicated that triol treatment at 20-40 µM induced apoptosis in all three cell lines. Micro-Western Arrays and traditional Western blotting methods indicated that triol treatment resulted in reduced expression of Akt1, phospho-Akt Ser473, phospho-Akt Thr308, PDK1, c-Myc, and Skp2 protein levels as well as accumulation of the cell cycle inhibitor p27(Kip). Triol treatment also resulted in reduced Akt1 protein expression in PC-3 xenografts. Overexpression of Skp2 in PC-3 cells partially rescued the growth inhibition caused by triol. Triol treatment suppressed migration and invasion of DU-145, PC-3, and CDXR-3 cells. The expression levels of proteins associated with epithelial-mesenchymal transition as well as focal adhesion kinase were affected by triol treatment in these cells. Triol treatment caused increased expression of E-cadherin protein levels but decreased expression of N-cadherin, vimentin, Slug, FAK, phospho-FAK Ser722, and phospho-FAK Tyr861 protein levels. Confocal laser microscopy revealed redistribution of β-actin and α-tubulin at the periphery of the CDXR-3 and DU-145 cells. Our observations suggest that triol may represent a promising therapeutic agent for advanced metastatic prostate cancer.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Lin
authors.forename: Chieh
authors.initials: C
authors.lastname: Huo
authors.forename: Li-Kuo
authors.initials: LK
authors.lastname: Kuo
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hiipakka
authors.forename: Richard Baker
authors.initials: RB
authors.lastname: Jones
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Lin
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Hung
authors.forename: Liang-Cheng
authors.initials: LC
authors.lastname: Su
authors.forename: Jen-Chih
authors.initials: JC
authors.lastname: Tseng
authors.forename: Ying-Yu
authors.initials: YY
authors.lastname: Kuo
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Wang
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Fukui
authors.forename: Yung-Hsi
authors.initials: YH
authors.lastname: Kao
authors.forename: John M
authors.initials: JM
authors.lastname: Kokontis
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Yeh
authors.forename: Linyi
authors.initials: L
authors.lastname: Chen
authors.forename: Shiaw-Der
authors.initials: SD
authors.lastname: Yang
authors.forename: Hsiao-Hui
authors.initials: HH
authors.lastname: Fu
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Kelvin K C
authors.initials: KK
authors.lastname: Tsai
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.forename: Chih-Pin
authors.initials: CP
authors.lastname: Chuu
mesh_terms: D000199:Actins / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002777:Cholestanols / Q000494:pharmacology*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D057093:Orphan Nuclear Receptors / Q000819:agonists; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020543:Proteome; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics; D015398:Signal Transduction; D014404:Tubulin / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D000199:Actins; D000728:Androgens; D000970:Antineoplastic Agents; D002777:Cholestanols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D020543:Proteome; D044786:S-Phase Kinase-Associated Proteins; D014404:Tubulin; C000474:cholestane-3,5,6-triol; D051057:Proto-Oncogene Proteins c-akt