PMID- 20420697
OWN - NLM
STAT- MEDLINE
DCOM- 20100730
LR  - 20211020
IS  - 1476-4598 (Electronic)
IS  - 1476-4598 (Linking)
VI  - 9
DP  - 2010 Apr 26
TI  - Hedgehog/Gli supports androgen signaling in androgen deprived and androgen 
      independent prostate cancer cells.
PG  - 89
LID - 10.1186/1476-4598-9-89 [doi]
AB  - BACKGROUND: Castration resistant prostate cancer (CRPC) develops as a consequence 
      of hormone therapies used to deplete androgens in advanced prostate cancer 
      patients. CRPC cells are able to grow in a low androgen environment and this is 
      associated with anomalous activity of their endogenous androgen receptor (AR) 
      despite the low systemic androgen levels in the patients. Therefore, the 
      reactivated tumor cell androgen signaling pathway is thought to provide a target 
      for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was 
      conditionally activated by androgen deprivation in androgen sensitive prostate 
      cancer cells and here we studied the potential for cross-talk between Hh and 
      androgen signaling activities in androgen deprived and androgen independent (AI) 
      prostate cancer cells. RESULTS: Treatment of a variety of androgen-deprived or AI 
      prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in 
      dose-dependent modulation of the expression of genes that are regulated by 
      androgen. The effect of cyclopamine on endogenous androgen-regulated gene 
      expression in androgen deprived and AI prostate cancer cells was consistent with 
      the suppressive effects of cyclopamine on the expression of a reporter gene 
      (luciferase) from two different androgen-dependent promoters. Similarly, 
      reduction of smoothened (Smo) expression with siRNA co-suppressed expression of 
      androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the 
      expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented 
      the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and 
      suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen 
      (R1881) restored growth to the AI cells in the presence of cyclopamine. 
      Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific 
      gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled 
      parental LNCaP cells to grow in androgen depleted medium. AR protein 
      co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates. 
      CONCLUSIONS: Collectively, our results indicate that Hh/Gli signaling supports 
      androgen signaling and AI growth in prostate cancer cells in a low androgen 
      environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests 
      that an interaction between these proteins might be the basis for Hedgehog/Gli 
      support of androgen signaling under this condition.
FAU - Chen, Mengqian
AU  - Chen M
AD  - The Ordway Research Institute, Albany, New York, USA.
FAU - Feuerstein, Michael A
AU  - Feuerstein MA
FAU - Levina, Elina
AU  - Levina E
FAU - Baghel, Prateek S
AU  - Baghel PS
FAU - Carkner, Richard D
AU  - Carkner RD
FAU - Tanner, Matthew J
AU  - Tanner MJ
FAU - Shtutman, Michael
AU  - Shtutman M
FAU - Vacherot, Francis
AU  - Vacherot F
FAU - Terry, Stephane
AU  - Terry S
FAU - de la Taille, Alexandre
AU  - de la Taille A
FAU - Buttyan, Ralph
AU  - Buttyan R
LA  - eng
GR  - R01 CA11618/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100426
PL  - England
TA  - Mol Cancer
JT  - Molecular cancer
JID - 101147698
RN  - 0 (Androgens)
RN  - 0 (GLI1 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Androgen)
RN  - 0 (Transcription Factors)
RN  - 0 (Veratrum Alkaloids)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - ZH658AJ192 (cyclopamine)
SB  - IM
MH  - Androgens/genetics/metabolism
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/drug effects/*genetics
MH  - Gene Expression/drug effects
MH  - Gene Expression Regulation, Neoplastic/drug effects/genetics
MH  - Hedgehog Proteins/genetics/*metabolism
MH  - Humans
MH  - Immunoprecipitation
MH  - Male
MH  - Prostatic Neoplasms/genetics/*metabolism
MH  - RNA, Small Interfering
MH  - Receptors, Androgen/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*physiology
MH  - Transcription Factors/genetics/*metabolism
MH  - Transfection
MH  - Veratrum Alkaloids/pharmacology
MH  - Zinc Finger Protein GLI1
PMC - PMC2873440
EDAT- 2010/04/28 06:00
MHDA- 2010/07/31 06:00
PMCR- 2010/04/26
CRDT- 2010/04/28 06:00
PHST- 2010/03/01 00:00 [received]
PHST- 2010/04/26 00:00 [accepted]
PHST- 2010/04/28 06:00 [entrez]
PHST- 2010/04/28 06:00 [pubmed]
PHST- 2010/07/31 06:00 [medline]
PHST- 2010/04/26 00:00 [pmc-release]
AID - 1476-4598-9-89 [pii]
AID - 10.1186/1476-4598-9-89 [doi]
PST - epublish
SO  - Mol Cancer. 2010 Apr 26;9:89. doi: 10.1186/1476-4598-9-89.