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Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression.
- Source :
-
The Prostate [Prostate] 2017 Feb; Vol. 77 (3), pp. 309-320. Date of Electronic Publication: 2016 Oct 24. - Publication Year :
- 2017
-
Abstract
- Background: 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).<br />Methods: 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.<br />Results: 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.<br />Conclusions: 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.<br /> (© 2016 Wiley Periodicals, Inc.)
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Androgen Antagonists pharmacology
Androgen Antagonists therapeutic use
Animals
Cytoskeletal Proteins genetics
Gene Knockdown Techniques methods
Humans
LIM Domain Proteins genetics
Male
Mice
Mice, Nude
Prostatic Neoplasms, Castration-Resistant drug therapy
Receptors, Androgen genetics
Adaptor Proteins, Signal Transducing antagonists & inhibitors
Adaptor Proteins, Signal Transducing biosynthesis
Cytoskeletal Proteins antagonists & inhibitors
Cytoskeletal Proteins biosynthesis
Disease Progression
LIM Domain Proteins antagonists & inhibitors
LIM Domain Proteins biosynthesis
Prostatic Neoplasms, Castration-Resistant metabolism
Receptors, Androgen biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0045
- Volume :
- 77
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Prostate
- Publication Type :
- Academic Journal
- Accession number :
- 27775154
- Full Text :
- https://doi.org/10.1002/pros.23269