YB-1: The key to personalised prostate cancer management?

Y-box-binding protein 1 (YB-1) is a DNA/RNA binding protein increasingly implicated in the regulation of cancer cell biology. Normally located in the cytoplasm, nuclear localisation in prostate cancer is associated with more aggressive, potentially treatment-resistant disease. This is attributed to the ability of YB-1 to act as a transcription factor for various target genes associated with androgen receptor signalling, survival, DNA repair, proliferation, invasion, differentiation, angiogenesis and hypoxia. This review aims to examine the clinical potential of YB-1 in the detection and therapeutic management of prostate cancer.

Capitalizing on Cancer Replication Stress by Preventing PAR Chain Turnover: A New Type of Synthetic Lethality.

Tumors resistant to PARP inhibitors frequently show signs of replication stress, with hyper-activated PARP. In this issue of Cancer Cell, Pillay et al. demonstrate that inhibiting PAR-chain turnover results in cell-cycle arrest, which is cytotoxic when combined with cell-cycle checkpoint inhibition and constitutes a novel cancer therapy.

Profiling of a panel of radioresistant prostate cancer cells identifies deregulation of key miRNAs.

BACKGROUND: miRNAs are increasingly associated with the aggressive phenotype of prostate tumours. Their ability to control radiobiologically-relevant cellular processes strengthens their potential as novel markers of response to radiation therapy. PURPOSE: To identify miRNAs associated with increased clonogenic survival following radiation exposure. MATERIAL AND METHODS: The miRNA expression profiles of a panel of 22RV1 cells with varying levels of radiosensitivities (hypoxic H-22Rv1 cells, RR-22Rv1 cells derived from WT-22Rv1 cells through 2-Gy fractionated repeated exposure, the associated aged matched cells (AMC-22Rv1) and the WT-22Rv1 cell lines) were generated and cross-analysed to identify common miRNAs associated with a radioresistant phenotype. RESULTS: Increased clonogenic survival following irradiation was associated with significant modifications in miRNA expression pattern. miR-221 (up) and miR-4284 (down) in RR-22Rv1 and MiR-31 and miR-200c in AMC-22Rv1 were the most uniquely significantly deregulated miRNAs when compared to WT-22Rv1 cells. miR-200c ranked as the most downregulated miRNAs in hypoxic, when compared to RR-22Rv1 cells. miR-200a was the only differentially expressed miRNA between RR-22Rv1 and AMC-22Rv1 cells. miR-210 yielded the highest fold change in expression in H-22Rv1, when compared to WT-22RV1 cells. CONCLUSION: This study identifies candidate miRNAs for the development of novel prognostic biomarkers for radiotherapy prostate cancer patients.

The Notch-3 receptor: A molecular switch to tumorigenesis?

The Notch pathway is a highly conserved pathway increasingly implicated with the progression of human cancers. Of the four existing receptors associated with the pathway, the deregulation in the expression of the Notch-3 receptor is associated with more aggressive disease and poor prognosis. Selective targeting of this receptor has the potential to enhance current anti-cancer treatments. Molecular profiling strategies are increasingly incorporated into clinical decision making. This review aims to evaluate the clinical potential of Notch-3 within this new era of personalised medicine.

Hypoxia regulates Notch-3 mRNA and receptor activation in prostate cancer cells.

The Notch-3 receptor is a recognized key regulator of vascular responses and is increasingly associated with tumorigenesis. Hypoxia-inducible factors activate specific signaling pathways such as Notch in a number of cellular models. This study aimed to evaluate the regulation of Notch-3 by hypoxia in prostate cancer cells. Notch-3 gene and protein expression was established in a panel of aerobic and hypoxic prostate cell lines in vitro, the CWR22 xenograft model and RNA extracted from low grade (Gleason score < = 6); high grade (Gleason score > = 7); non-hypoxic (low HIF, low VEGF); hypoxic (high HIF, high VEGF) patient FFPE specimens. NOTCH-3 was upregulated in PC3 (3-fold), 22Rv1 (4.1-fold) and DU145 (3.8-fold) but downregulated in LnCaP (12-fold) compared to the normal cell lines. NOTCH-3 expression was modified following hypoxic exposure in these cells. NOTCH-3 was upregulated (2.2-fold) in higher grade and hypoxic tumors, when compared to benign and aerobic pools. In the CWR22 xenograft model, Notch-3 expression was restored in castrate resistant tumors. Nuclear translocation of the Notch-3 intracellular domain was no longer detected following exposure of cells to hypoxia but not associated with a change in expression of HES-1. Our data further identifies Notch-3 as a potentially key hypoxic-responsive member of the Notch pathway in prostate tumorigenesis.

Isogenic radiation resistant cell lines: development and validation strategies.

PURPOSE: The comparison of cell lines with differing radiosensitivities and their molecular response to radiation exposure has been used in a number of human cancer models to study the molecular response to radiation. This review proposes to analyze and compare the protocols used by investigators for the development and validation of these isogenic models of radioresistance. CONCLUSION: There is large variability in the strategies used to generate and validate isogenic models of radioresistance. Further characterization of these models is required.

NUMB inhibition of NOTCH signalling as a therapeutic target in prostate cancer.

Prostate cancer is among the most prevalent life-threatening cancers diagnosed in the male population today. Various methods have been exploited in an attempt to treat this disease but these treatments, alongside preventative tactics, have been insufficient to control mortality rates and have usually resulted in detrimental adverse events. An opportunity to devise more-specific and potentially more-effective approaches for the eradication of prostate tumours can be found by targeting specific biological pathways. NUMB (protein numb homologue), a key regulator of cell fate, represents an attractive, actionable target in prostate cancer. NUMB participates in the observed deregulation of NOTCH (neurogenic locus notch homologue protein) signalling in prostate tumours, and the NUMB-NOTCH interaction regulates cell fate. NUMB has potential both as a target for control of prostate tumorigenesis and as a biomarker for identification of patients with prostate cancer who are likely to benefit from NOTCH inhibition.