There is growing evidence showing prostate cancer cells have perturbed cholesterol homeostasis, accumulating cholesterol to promote cell-growth. Consequently, cholesterol lowering drugs like statins are being evaluated in prostate cancer treatment. Furthermore, natural products such as betulin (from birch tree bark) and tocotrienol (a minor form of Vitamin E) have been shown to lower cholesterol levels. Using these drugs and oxysterols, we determine which aspects of cholesterol homeostasis should be targeted in prostate cancer –e.g., cellular cholesterol levels are increased by the transcription factor Sterol-Regulatory Element Binding Protein isoform 2 (SREBP-2), whereas the Liver X Receptor (LXR) promotes cholesterol efflux. Whilst betulin exerted non-specific effects on cell viability, tocotrienols produced a strong direct correlation between SREBP-2 activity and cell viability. Mechanistically, tocotrienols lowered SREBP-2 activity by degrading mature SREBP-2 independently of the proteasome. In contrast, no correlation was seen between LXR activity and cell viability, implying SREBP-2 is a better target than LXR for prostate cancer treatment. Lastly, androgen-dependent and -independent LNCaP cells were both sensitive to tocotrienols. Overall, this suggests that tocotrienols and other drugs targeting the SREBP-2 pathway are a potential therapeutic option for prostate cancer.
