Abstract
BackgroundProstate cancer is initially dependent on androgens for survival and growth, making hormonal therapy the cornerstone treatment for late-stage tumors. However, despite initial remission, the cancer will inevitably recur. The present study was designed to investigate how androgen-dependent prostate cancer cells eventually survive and resume growth under androgen-deprived and antiandrogen supplemented conditions. As model system, we used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu1 and PC346Flu2.Methodology/Principal FindingsMicroarray technology was used to analyze differences in gene expression between the androgen-responsive and therapy-resistant PC346 cell lines. Microarray analysis revealed 487 transcripts differentially-expressed between the androgen-responsive and the therapy-resistant cell lines. Most of these genes were common to all three therapy-resistant sublines and only a minority (∼5%) was androgen-regulated. Pathway analysis revealed enrichment in functions involving cellular movement, cell growth and cell death, as well as association with cancer and reproductive system disease. PC346DCC expressed residual levels of androgen receptor (AR) and showed significant down-regulation of androgen-regulated genes (p-value = 10−7). Up-regulation of VAV3 and TWIST1 oncogenes and repression of the DKK3 tumor-suppressor was observed in PC346DCC, suggesting a potential AR bypass mechanism. Subsequent validation of these three genes in patient samples confirmed that expression was deregulated during prostate cancer progression.Conclusions/SignificanceTherapy-resistant growth may result from adaptations in the AR pathway, but androgen-independence may also be achieved by alternative survival mechanisms. Here we identified TWIST1, VAV3 and DKK3 as potential players in the bypassing of the AR pathway, making them good candidates as biomarkers and novel therapeutical targets.
Highlights
Prostate cancer (PCa) is the second leading cause of male cancer deaths in the Western countries and an increasing problem in those adopting Western lifestyle and diet
Consistent with this hypothesis, paracrine growth factors that are normally secreted by prostate stroma cells, such as epidermal growth factor (EGF), insulin-like growth factor 1 (IGF1), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) or interleukin 6 (IL6), are found to be overexpression in hormone-refractory cancer in association with a switch to autocrine production by cancer epithelial cells [16]
Each of the therapy-resistant sublines were cultured in their respective selection medium and hybridized on the microarrays, together with the parental androgen-responsive PC346C
Summary
Prostate cancer (PCa) is the second leading cause of male cancer deaths in the Western countries and an increasing problem in those adopting Western lifestyle and diet. Since the AR pathway is involved in processes of cellular differentiation and prostate maturation, it is tempting to suggest that PCa cells may eventually gain growth advantage by inhibiting the AR induced differentiation Prompted by these results, we focused the present study on alternative survival and growth pathways, which are independent of AR activation. Autocrine production of growth factors or its receptors, activation of oncogenes and inhibition of tumor-suppressor genes are all possible mechanisms for bypassing the AR pathway Consistent with this hypothesis, paracrine growth factors that are normally secreted by prostate stroma cells, such as epidermal growth factor (EGF), insulin-like growth factor 1 (IGF1), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF) or interleukin 6 (IL6), are found to be overexpression in hormone-refractory cancer in association with a switch to autocrine production by cancer epithelial cells [16]. We used the androgen-responsive PC346C cell line and its therapy-resistant sublines: PC346DCC, PC346Flu and PC346Flu
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