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Abstract
Prostate cancer (PCa) is the most common cancer in men in developed countries. Epidemiological studies have associated high blood-cholesterol levels with an increased risk of PCa, whilst cholesterol-lowering drugs (statins) reduce the risk of advanced PCa. Furthermore, PCa cells have been found to accumulate large amounts of cholesterol. Why and how does this happen? This thesis examines the regulation of cholesterol levels in PCa cells, aiming to address how cholesterol accumulates and whether this could provide a novel therapeutic target.
Using molecular biology techniques, we initially showed that laboratory PCa cell-lines differed in their responsiveness to changing cholesterol levels. In particular, there were differences in the regulation of two master transcription factors: (1) sterol regulatory element-binding protein 2 (SREBP-2), which increases cholesterol levels, and (2) liver X receptor (LXR), which reduces cholesterol levels. From this, we found that cholesterol accumulation was stimulated by signals that promote PCa cell-growth for example, male sex hormones act via the androgen receptor (AR) to enhance SREBP-2 activity and inhibit LXR, increasing cellular cholesterol levels in a concerted fashion. To explore this further, we developed a castration-resistant PCa progression model, finding that although AR activity changes with progression, this has little effect on cholesterol homeostasis, suggesting compensation by other regulators. This maintenance of cholesterol homeostasis supports its potential as a drug target.
To address which aspects of cholesterol homeostasis should be targeted in PCa, we used tocotrienols, a form of vitamin E previously found to selectively target PCa cells in vitro. We found that tocotrienols degrade SREBP-2 by a novel mechanism. In turn, we found that SREBP-2 activity determined resistance to tocotrienols in cell viability assays. Furthermore, both parental (androgen-dependent) and late-stage (castration-resistant) cells from our progression model were sensitive to SREBP-2 manipulation by tocotrienols. In contrast, toggling LXR activity had little effect on cell viability, suggesting that the SREBP-2 pathway could be a better target for PCa.
This thesis presents a picture that cholesterol metabolism is important for PCa development: growth-promoting factors stimulate cholesterol accumulation, which in turn presents a possible target for chemotherapy.