Figure 1.

A. Features of advanced Castrate Resistant Prostate Cancer cells. The elevated cholesterol phenotype of advanced prostate cancer affects growth signaling, apoptosis and steroidogenesis. The LnCaP cell line C81 was derived from the C33 clone by extended serial passage and has acquired an altered program of gene expression that permits androgen synthesis. We propose this includes a loss of TERE1 expression. This manuscript describes the role of TERE1 and its novel link to SXR-mediated mechanisms of regulating sterol accumulation in cells. B. TERE1 at the nexus of cholesterol synthesis, storage, and efflux: Overview of vitamin K-2 effects on cellular metabolism. APOE is a carrier of vitamin K-1, cholesterol, and triglycerides that interacts with TERE1 and is involved in K-1 delivery as well as lipid recycling and efflux. TERE1 converts K-1 to K-2 at multiple locations: golgi, ER, and mitochondria. In ER and golgi TERE1 may interact with HMGCR and SOAT1 thus affect cholesterol synthesis and storage. Based on redox-cyling the K-2 and K-3 quinones may create reactive oxygen species, ROS, and nitric oxide, NO. In mitochondria K-2 plays a role in apoptosis, electron transport and may play a role in mitochondrial bioenergetics in anaerobic environments. TERE1 synthesis of vitamin K-2 creates a potent endogenous activator of the SXR nuclear receptor, which traverses to the nucleus with RXR and is a master regulator of endobiotic lipid and fatty acid homeostasis, Phase I and II enzymes and transporters involved in drug metabolism/clearance, and efflux of cholesterol and steroids. In this regard, TERE1 elicits an anti-sterol program that may reverse the elevated cholesterol phenotype of CRPC.