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The modulation of androgen action in prostate cancer by exogenous chemicals, efflux transporter P-glycoprotein and Y-box binding protein-1

University of British Columbia

Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer deaths in Canada. Human prostate carcinomas are often androgen-dependent and respond to androgen withdrawal therapy by temporary regression, followed by androgen- .independent recurrence. These well-established features of prostate cancer strongly suggest that androgens play a major role in prostate carcinogenesis. The overall goal of the research described in this thesis is to gain a more comprehensive understanding of the mechanisms modulating androgen action in prostate cancer cells. This focused on the influence of exogenous chemicals, the efflux transporter P-glycoprotein and the multi-functional transcription factor Y-box Binding Protein-1. Epidemiological evidence, based on agricultural occupational exposures, instigated experimental work that showed pesticides have the potential to mimic or antagonize hormone action, in many cases through androgen receptor binding and interfering with transcriptional activity, thus are capable of disrupting the male hormone-signaling pathway. Furthermore, in prostate cancer cells, androgen responsiveness is modulated by Pgp activity and expression. The biological consequences of increased Pgp expression are decreased androgen accumulation and a corresponding decrease in androgen-regulated transcriptional activity and prostate-specific antigen gene expression. Experimental evidence further supports the hypothesis that early in prostate cancer progression, increased YB-1 expression increases Pgp activity, which consequently lowers androgen levels in prostate tumour cells. Suppression of androgen levels may activate cell survival pathways and lead to an adaptive survival advantage of androgen-independent prostate cancer cells following androgen ablation therapy. Understanding the complex molecular mechanisms by which prostate cancer cells can control androgen function, and how prostate cancer cells evade apoptotic death, provides a paradigm to explain the relationship between androgen action and chemotherapeutic resistance. As a result, the final objective investigated the effects of YB-1 knockdown using antisense oligonucleotides in vitro, and in vivo after androgen withdrawal in human LNCaP prostate cancer tumour xenografts, with the aim of suppressing cellular proliferation and increasing chemosensitivity. Intratumoral injection of 2'-0-(methoxy)ethyl ribose-modified YB-1 ASO and paclitaxel incorporated into a biodegradable, controlled-release formulation in castrated mice delayed Al progression. These results suggest that YB-1 may be a promising target for the treatment of prostate cancer based on a strategy of inhibiting cellular proliferation. Our understanding of the molecular links between androgen action, tumorigenesis, apoptosis, and drug resistance provides the foundation for a new era of targeted cancer therapy.

Text

2010-01-16

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http://hdl.handle.net/2429/18475

Pathology

University of British Columbia

UBCV

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