Abstract
The exact biological mechanism governing the radioresistant phenotype of prostate tumours at a high risk of recurrence despite the delivery of advanced radiotherapy protocols remains unclear. This study analysed the protein expression profiles of a previously generated isogenic 22Rv1 prostate cancer model of radioresistance using DigiWest multiplex protein profiling for a selection of 90 signalling proteins. Comparative analysis of the profiles identified a substantial change in the expression of 43 proteins. Differential PARP-1, AR, p53, Notch-3 and YB-1 protein levels were independently validated using Western Blotting. Pharmacological targeting of these proteins was associated with a mild but significant radiosensitisation effect at 4Gy. This study supports the clinical relevance of isogenic in vitro models of radioresistance and clarifies the molecular radiation response of prostate cancer cells.
Highlights
Prostate tumours not controlled by radiation therapy[1] may present with radiation protective biological characteristics[2] whose pre-treatment identification has the potential to predict treatment outcomes and initiate the development of novel, more aggressive, treatment options
The effects of radiation exposure on cancer cells and subsequent regulation of cell fate has been linked to DNA damage induction[4,5], all known cancer hallmarks[3], and the tumour microenvironment[26]
This study proposed to compare the protein expression profiles for a selection of signaling proteins involved in these biological processes in a pre-existing isogenic model of 22Rv1 prostate cancer cells[23]
Summary
Prostate tumours not controlled by radiation therapy[1] may present with radiation protective biological characteristics[2] whose pre-treatment identification has the potential to predict treatment outcomes and initiate the development of novel, more aggressive, treatment options. YB-1 is a multifunctional protein whose expression increases with prostate cancer progression and is predictive of recurrence following surgery[21] It is involved in both the transcriptional and translational regulation of gene expression, and controls almost all DNA and mRNA dependent processes in the cell such as cellular differentiation, proliferation and stress response[22]. Exposure to fractionated radiation progressively selected for a 22Rv1 prostate carcinoma cell population enriched in S-phase cells, less susceptible to DNA damage, radiation-induced apoptosis and acquired enhanced migration potential, when compared to wild type and aged-matched control 22Rv1 cells[23] These enhanced radioprotective oncogenic properties, observed in isogenic models of other disease sites[3], were associated with an altered miRNA profile common to that of 22Rv1 cells exposed to hypoxia, a known factor associated with radioresistance[24,25]. Pilot analysis in pre-treatment biopsies of prostate cancer patients treated with radiation therapy for the first time implicates the YB-1 protein in treatment failure
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