Abstract
Approximately one in six men are diagnosed with Prostate Cancer every year in the Western world. Although it can be well managed and non-life threatening in the early stages, over time many patients cease to respond to treatment and develop castrate resistant prostate cancer (CRPC). CRPC represents a clinically challenging and lethal form of prostate cancer. Progression of CRPC is, in part, driven by the ability of cancer cells to alter their metabolic profile during the course of tumourgenesis and metastasis so that they can survive in oxygen and nutrient-poor environments and even withstand treatment. This work was carried out as a continuation of a study aimed towards gaining greater mechanistic understanding of how conditions within the tumour microenvironment impact on both androgen sensitive (LNCaP) and androgen independent (LNCaP-abl and LNCaP-abl-Hof) prostate cancer cell lines. Here we have applied technically robust and reproducible label-free liquid chromatography mass spectrometry analysis for comprehensive proteomic profiling of prostate cancer cell lines under hypoxic conditions. This led to the identification of over 4,000 proteins – one of the largest protein datasets for prostate cancer cell lines established to date. The biological and clinical significance of proteins showing a significant change in expression as result of hypoxic conditions was established. Novel, intuitive workflows were subsequently implemented to enable robust, reproducible and high throughput verification of selected proteins of interest. Overall, these data suggest that this strategy supports identification of protein biomarkers of prostate cancer progression and potential therapeutic targets for CRPC.
Highlights
Prostate cancer (PCa) is the second most common cancer in men worldwide
Prolyl hydroxylases are central to oxygen-sensing pathways and previous studies have shown that DMOG can be effectively used as a means of mimicking hypoxia through activation of the HIF pathway under non-hypoxic conditions (21% O2) [22]
Cells were incubated in 1mM DMOG for 8 hours to allow for investigation of protein changes that may be reflective of an acute response to hypoxic conditions
Summary
The incidence of PCa is high, most men have an indolent form of disease that can be effectively treated with radical prostatectomy, androgen deprivation therapy (ADT), radiotherapy or combinations thereof [1, 2]. In PCa, signs of hypoxia and metabolic stress in the prostate tumour tissue are exacerbated following ADT, it has been suggested that this hypoxic microenvironment can, enhance the transcriptional activity of the androgen receptor (AR) [3, 9, 10]. Given the importance of androgen-regulated proteins in PCa development and progression, it is anticipated that further characterization of the role of hypoxia and androgen sensitivity in PCa progression may provide further insight into the mechanisms that drive aggressive, treatment resistant CRPC [11]
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