title: Galbanic acid decreases androgen receptor abundance and signaling and induces G1 arrest in prostate cancer cells.
abstract: Androgen receptor (AR) signaling is crucial for the genesis and progression of prostate cancer (PCa). We compared the growth responses of AR(+) LNCaP and LNCaP C4-2 vs. AR(-) DU145 and PC-3 PCa cell lines to galbanic acid (GBA) isolated from the resin of medicinal herb Ferula assafoetida and assessed their connection to AR signaling and cell cycle regulatory pathways. Our results showed that GBA preferentially suppressed AR(+) PCa cell growth than AR(-) PCa cells. GBA induced a caspase-mediated apoptosis that was attenuated by a general caspase inhibitor. Subapoptotic GBA downregulated AR protein in LNCaP cells primarily through promoting its proteasomal degradation, and inhibited AR-dependent transcription without affecting AR nuclear translocation. Whereas docking simulations predicted binding of GBA to the AR ligand binding domain with similarities and differences with the AR antagonist drug bicalutamide (Bic), LNCaP cell culture assays did not detect agonist activity of GBA. GBA and Bic exerted greater than additive inhibitory effect on cell growth when used together. Subapoptotic GBA induced G(1)  arrest associated with an inhibition of cyclin/CDK4/6 pathway, especially cyclin D(1)  without the causal involvement of cyclin-dependent kinase (CDK) inhibitory proteins P21(Cip1)  and P27(Kip1) . In summary, the novelty of GBA as an anti-AR compound resides in the distinction between GBA and Bic with respect to AR protein turnover and a lack of agonist effect. Our observations of anti-AR and cell cycle arrest actions plus the anti-angiogenesis effect reported elsewhere suggest GBA as a multitargeting drug candidate for the prevention and therapy of PCa.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Kwan-Hyun
authors.initials: KH
authors.lastname: Kim
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Yinglu
authors.initials: Y
authors.lastname: Guo
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lü
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D056741:Cyclin D / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005309:Ferula / Q000737:chemistry; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014105:Tosyl Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D000813:Anilides; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D003374:Coumarins; D056741:Cyclin D; D050684:E2F Transcription Factors; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; D014105:Tosyl Compounds; C048972:galbanic acid; C053541:bicalutamide; D008156:Luciferases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D020169:Caspases