title: Inhibition of hedgehog and androgen receptor signaling pathways produced synergistic suppression of castration-resistant prostate cancer progression.
abstract: Metastatic prostate cancer is initially treated with androgen ablation therapy, which causes regression of androgen-dependent tumors. However, these tumors eventually relapse resulting in recurrent castration-resistant prostate cancer (CRPC). Currently, there is no effective therapy for CRPC and the molecular mechanisms that lead to the development of CRPC are not well understood. Here, we evaluated the hypothesis that combined inhibition of Hedgehog (Hh) and androgen receptor (AR) signaling will synergistically attenuate the growth of CRPC in vitro and in vivo. Androgen deprivation induced full-length androgen receptor protein levels in CRPC cells, but decreased its nuclear localization and transcriptional activity. However, androgen deprivation also increased a truncated form of androgen receptor (lacking ligand-binding domain) that possessed transcriptional activity in CRPC cells. Androgen deprivation also promoted the expression of Hh signaling components in CRPC cells, xenograft tumors, and the prostate glands of castrated mice. Importantly, although inhibition of either Hh or androgen receptor signaling alone was only moderately effective in blocking CRPC cell growth, combination of an Hh pathway inhibitor and a noncompetitive androgen receptor inhibitor synergistically suppressed the growth of CRPC cells in vitro and in vivo. Finally, noncompetitive inhibition of androgen receptor, but not competitive inhibition, was effective at limiting the activity of truncated androgen receptor leading to the inhibition of CRPC.
  
  
  CONCLUSIONS
  Combined therapy using Hh inhibitors and a non-competitive AR inhibitor may limit CRPC growth.
authors.affiliation: Department of Cellular & Structural Biology, University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7762, San Antonio, TX 78229-3900. sunl@uthscsa.edu.
authors.forename: Pramod S
authors.initials: PS
authors.lastname: Gowda
authors.forename: Jianhong D
authors.initials: JD
authors.lastname: Deng
authors.forename: Sweta
authors.initials: S
authors.lastname: Mishra
authors.forename: Abhik
authors.initials: A
authors.lastname: Bandyopadhyay
authors.forename: Sitai
authors.initials: S
authors.lastname: Liang
authors.forename: Shu
authors.initials: S
authors.lastname: Lin
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Sun
mesh_terms: D059002:Androgen Receptor Antagonists / Q000627:therapeutic use; D000728:Androgens / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D053823:Hedgehog Proteins; D011944:Receptors, Androgen