Abstract 469: CD151 and cell motility in prostate cancer

Abstract

Prostate cancer (PCa) is one of the leading causes of cancer death in men. CD151 is a member of the tetraspanin family and is associated with regulation of migration of normal and tumour cells via cell surface microdomain formation. Previous studies from our laboratory revealed that expression of CD151 differs across histological grades of PCa and high levels of expression are linked to shorter survival, independent of Gleason score1. In vitro motility assays of human PCa cell lines suggest CD151 is a motility promoter2. We have sought to develop a number of CD151 inhibitors and examine their ability to modulate prostate cancer motility and metastasis. The human PCa cell line, LNCaP (low endogenous level of CD151), transfected with CD151 shows increased motility and invasion compared to control LNCaP, whilst CD151 siRNA knock-down (KD) of PC-3 cells (high endogenous level of CD151), reduces motility compared to control PC-3. We have conducted in silico screening with compounds predicted to bind a model of the large extracellular domain (EC2) of CD151 and found that a number of these small molecules possess bioactivity in vitro and in vivo in inhibiting prostate cancer motility and progression. LNCaP growth and migration was confirmed by stimulating with 1 and 10 nM DHT at 24 hrs in charcoal stripped FBS. It was found that cell proliferation and motility of LNCaP cells was significantly increased after stimulation by 10 nM DHT at 24 hrs (p<0.01) and 48hrs (p<0.01), whilst DHT had minimal effect on control PC-3 and DU-145 cells. We have also analyzed a set of whole genome microarray expression data from PCa cell lines PC-3 and CD151 KD PC-3, and identified differentially expressed genes linked to CD151. Significant changes were seen in 172 genes after CD151 KD in PC-3 cells. We examined the protein interaction networks of our differentially expressed genes using Cytoscape3. Functional network analysis revealed high level of connectivity surrounding genes involved in transcriptional regulation, microtubule-based movement and protein folding and complex formation. CD151 is an important promoter of cell migration and metastatic disease in PCa and may serve as a target for a novel class of anti-metastatic therapeutic agents. A systems biology approach allows for improved mechanistic interpretation of biological data and may facilitate identification of other therapeutic targets. 1 Ang J et al. Cancer Epidemiol Biomarkers & Prevention (2004) 13: 1717-21 2 Ang J et al. Oncology Reports (2010) 24(6): 1593-1597 3 Shannon P et al. Genome research (2003) 13: 2498-2504 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 469. doi:1538-7445.AM2012-469

Role of Transmembrane 4 L Six Family 1 in the Development and Progression of Cancer

“…Almost all tetraspanins contain palmitoylated cysteine near the membrane. All tetraspanins include a highly conserved Cys-Cys-Gly (CCG) motif located behind the B helix of the EC2 loop (Detchokul et al, 2014). However, TM4SFs has several differences from other tetraspanin superfamily members.…”

“…Both can form tetraspanin-enriched microdomains (TEMs or TERMs) through their interaction with other proteins, including integrins, receptor tyrosine kinases, immunoproteins, lipid kinases, and PDZ-domain-containing proteins (Lekishvili et al, 2008). TEMs play crucial roles in modulating various cellular functions, such as cell motility, adhesion, propagation, migration, and invasion through signaling pathways including activation of PI3kinase and Cdc42 (Lee et al, 2011;Detchokul et al, 2014). On the cell surface, tetraspanins exist as dimers, e.g., CD9-CD9 and CD151-CD81, suggesting that the dimer might be the basic unit of TEM (Kitadokoro et al, 2002).…”