Honokiol InhibitsAndrogen ReceptorActivity in Prostate Cancer Cells

• Authors: Eun-Ryeong Hahm, University of Pittsburgh; A. Isabella Karlsson, Emory University; Michael Y. Bonner, Emory University; Jack Arbiser, Emory University; Shivendra V. Singh, University of Pittsburgh
• Journal Title: Prostate
• Volume: Volume 74, Number 4
• Publisher: Wiley: 12 months | 2014-04-01, Pages 408-420
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/pros.22762
• Subjects: Health Sciences, Oncology; Health Sciences, Medicine and Surgery; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Endocrinology & Metabolism; Urology & Nephrology; honokiol; alternative medicine; androgen receptor; prostate cancer; NF-KAPPA-B; ANDROGEN RECEPTOR; TRANSCRIPTIONAL REPRESSION; LIPOSOMAL HONOKIOL; DIALLYL TRISULFIDE; INHIBITION; APOPTOSIS; GROWTH; ASSOCIATION; CONSTITUENT

Abstract

BACKGROUND: We have shown previously that honokiol (HNK), a bioactive component of the medicinal plant Magnolia officinalis, inhibits growth of human prostate cancer cells in vitro and in vivo. However, the effect of HNK on androgen receptor (AR) signaling has not been studied. METHODS: LNCaP, C4-2, and TRAMP-C1 cells were used for various assays. Trypan blue dye exclusion assay or clonogenic assay was performed for determination of cell viability. The effects of HNK and/or its analogs on protein levels of AR and its target gene product prostate specific antigen (PSA) were determined by western blotting. RNA interference of p53 was achieved by transient transfection. Reverse transcription-polymerase chain reaction was performed for mRNA expression of AR. Nuclear level of AR was visualized by microscopy. Apoptosis was quantified by DNA fragmentation assay or flow cytometry after Annexin V-propidium iodide staining. RESULTS: HNK and its dichloroacetate analog (HDCA) were relatively more effective in suppressing cell viability and AR protein level than honokiol epoxide or biseugenol. Nuclear translocation of AR stimulated by a synthetic androgen (R1881) was markedly suppressed in the presence of HNK. Downregulation of AR protein resulting from HNK exposure was attributable to transcriptional repression as well as proteasomal degradation. HNK-mediated suppression of AR protein was maintained in LNCaP cells after knockdown of p53 protein. HNK-induced apoptosis was not affected by R1881 treatment. CONCLUSIONS: The present study demonstrates, for the first time, that HNK inhibits activity of AR in prostate cancer cells regardless of the p53 status.