title: Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression.
abstract: LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO).
  
  
  
  A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies.
  
  
  
  The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts.
  
  
  
  These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. © 2016 Wiley Periodicals, Inc.
authors: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Takashi
authors: T
authors: Dejima
authors: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Kenjiro
authors: K
authors: Imada
authors: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Ario
authors: A
authors: Takeuchi
authors: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Masaki
authors: M
authors: Shiota
authors: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Jeffrey
authors: J
authors: Leong
authors: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Tabitha
authors: T
authors: Tombe
authors: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Kevin
authors: K
authors: Tam
authors: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ladan
authors: L
authors: Fazli
authors: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Seiji
authors: S
authors: Naito
authors: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Martin E
authors: ME
authors: Gleave
authors: Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Christopher J
authors: CJ
authors: Ong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D000726:Androgen Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D018450:Disease Progression; D055785:Gene Knockdown Techniques / Q000379:methods; D006801:Humans; D060588:LIM Domain Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism*; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C410798:AR protein, human; D048868:Adaptor Proteins, Signal Transducing; D000726:Androgen Antagonists; D003598:Cytoskeletal Proteins; C096353:LASP1 protein, human; D060588:LIM Domain Proteins; D011944:Receptors, Androgen
keywords: AR; LASP1; castration resistant prostate cancer