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

Nadenla, Sandeep K., Hazan, Allon, Ward, Matt, Harper, Lisa J., Moutasim, Karwan, Bianchi, Lucia S., Naase, Mahmoud, Ghali, Lucy ORCID logoORCID: https://orcid.org/0000-0003-3410-6615, Thomas, Gareth J., Prowse, David M., Philpott, Michael P. and Neill, Graham W. (2011) GLI1 confers profound phenotypic changes upon LNCaP prostate cancer cells that include the acquisition of a hormone independent state. PLoS One, 6 (5) , e20271. pp. 1-13. ISSN 1932-6203 [Article] (doi:10.1371/journal.pone.0020271)

[img]
Preview
PDF - Published version (with publisher's formatting)
Available under License Creative Commons Attribution 4.0.

Download (4MB) | Preview

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, beta1-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.

Item Type: Article
Research Areas: A. > School of Science and Technology > Natural Sciences > Biomarkers for Cancer group
Item ID: 7949
Notes on copyright: Copyright: © 2011 Nadendla et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Useful Links:
Depositing User: Repository team
Date Deposited: 21 Jun 2011 13:32
Last Modified: 30 Nov 2022 00:50
URI: https://eprints.mdx.ac.uk/id/eprint/7949

Actions (login required)

View Item View Item

Statistics

Activity Overview
6 month trend
319Downloads
6 month trend
468Hits

Additional statistics are available via IRStats2.