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GLI1 confers profound phenotypic changes upon LNCaP prostrate cancer cells that include the acquisition of a hormone independent state

Nadendla, Sandeep K., Hazan, Allon, Ward, Matt, Harper, Lisa J., Moutasim, Karwan, Bianchi, Lucia S., Naase, Mahmoud, Ghali, Lucy, Thomas, Gareth J., Prowse, David M., Philpott, Michael P. and Neill, Graham W. (2011) GLI1 confers profound phenotypic changes upon LNCaP prostrate cancer cells that include the acquisition of a hormone independent state PLoS ONE, 6, (5), e20271-[13pp]. (doi:10.1371/journal.pone.0020271). (PMID:21633508).

Record type: Article

Abstract

The GLI (GLI1/GLI2) transcription factors have been implicated in the development and progression of prostate cancer although our understanding of how they actually contribute to the biology of these common tumours is limited. We observed that GLI reporter activity was higher in normal (PNT-2) and tumourigenic (DU145 and PC-3) androgen-independent cells compared to androgen-dependent LNCaP prostate cancer cells and, accordingly, GLI mRNA levels were also elevated. Ectopic expression of GLI1 or the constitutively active ?NGLI2 mutant induced a distinct cobblestone-like morphology in LNCaP cells that, regarding the former, correlated with increased GLI2 as well as expression of the basal/stem-like markers CD44, ?1-integrin, ?Np63 and BMI1, and decreased expression of the luminal marker AR (androgen receptor). LNCaP-GLI1 cells were viable in the presence of the AR inhibitor bicalutamide and gene expression profiling revealed that the transcriptome of LNCaP-GLI1 cells was significantly closer to DU145 and PC-3 cells than to control LNCaP-pBP (empty vector) cells, as well as identifying LCN2/NGAL as a highly induced transcript which is associated with hormone independence in breast and prostate cancer. Functionally, LNCaP-GLI1 cells displayed greater clonal growth and were more invasive than control cells but they did not form colonies in soft agar or prostaspheres in suspension suggesting that they do not possess inherent stem cell properties. Moreover, targeted suppression of GLI1 or GLI2 with siRNA did not reverse the transformed phenotype of LNCaP-GLI1 cells nor did double GLI1/GLI2 knockdowns activate AR expression in DU145 or PC-3 cells. As such, early targeting of the GLI oncoproteins may hinder progression to a hormone independent state but a more detailed understanding of the mechanisms that maintain this phenotype is required to determine if their inhibition will enhance the efficacy of anti-hormonal therapy through the induction of a luminal phenotype and increased dependency upon AR function.

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Published date: 25 May 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 339671
URI: http://eprints.soton.ac.uk/id/eprint/339671
ISSN: 1932-6203
PURE UUID: 7f3ab5e0-dce7-476a-8eb2-d2f129b8a985

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Date deposited: 29 May 2012 10:29
Last modified: 18 Jul 2017 05:53

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Contributors

Author: Sandeep K. Nadendla
Author: Allon Hazan
Author: Matt Ward
Author: Lisa J. Harper
Author: Karwan Moutasim
Author: Lucia S. Bianchi
Author: Mahmoud Naase
Author: Lucy Ghali
Author: David M. Prowse
Author: Michael P. Philpott
Author: Graham W. Neill

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