UBC Theses and Dissertations
Cholesterol metabolism as a target in castration-resistant prostate cancer Gordon, Jacob
Despite clinical benefits of existing prostate cancer treatments, patients continue to develop therapeutic resistance. Persistence of androgen receptor pathway activity is attributed to several mechanisms associated with resistance, including intratumoral androgen receptor agonist synthesis from the precursor cholesterol. Cholesterol has been correlated to poor outcomes in patients and clinically the use of cholesterol synthesis inhibitors, statins, improves prostate cancer survival. The expression of the high-density lipoprotein-cholesterol receptor, scavenger receptor B1 (SR-B1), is elevated in castration-resistant prostate cancer models and has been linked to poor survival of patients. The overarching hypothesis of this thesis is that cholesterol modulation, through either synthesis or uptake inhibition, will impact essential signaling processes impeding the proliferation of prostate cancer. Clinically statin use was found to improve the overall survival of metastatic castration-resistant prostate cancer patients receiving the androgen synthesis inhibitor abiraterone. In vivo experiments demonstrated the ability of statins to impede post-castration biochemical recurrence and reduce tumor growth and androgen receptor agonist synthesis in LNCaP-derived xenograft tumors. SR-B1 was found to be overexpressed in clinical samples from both local and metastatic prostate cancer. Antagonism of SR-B1 in steroid responsive C4-2 cells decreased cholesterol uptake and growth and induced cell cycle arrest. Initially attributed to an observed decrease in de novo steroid synthesis and androgen receptor activity, the inability of exogenous steroid to restore cellular proliferation or androgen receptor activity indicated steroid independent cellular arrest. As such, cellular stress and nutrient deprivation responses were assessed and SR-B1 antagonism was found to induce both autophagy and endoplasmic reticulum stress markers. Given the steroid-independent manner of SR-B1 antagonism mediated cellular arrest, the effects of SR-B1 antagonism on androgen independent PC-3 cells was assessed and found to result in robust cellular death in vitro and decreased growth of xenograft tumors. These findings demonstrate that the reduction of cellular cholesterol availability can impede prostate cancer proliferation through both decreased steroid-synthesis and steroid-independent mechanisms providing a potential therapeutic target for the treatment of prostate cancer.
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