Castrate-Resistant
Prostate Cancer (CRPC) is characterized by persistent
androgen receptor-driven
tumor growth in the apparent absence of systemic
androgens. Current evidence suggests that CRPC cells can produce their own
androgens from endogenous
sterol precursors that act in an intracrine manner to stimulate
tumor growth. The mechanisms by which CRPC cells become steroidogenic during
tumor progression are not well defined. Herein we describe a novel link between the
elevated cholesterol phenotype of CRPC and the TERE1
tumor suppressor protein, a
prenyltransferase that synthesizes
vitamin K-2, which is a potent endogenous
ligand for the SXR
nuclear hormone receptor. We show that 50% of primary and metastatic
prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and
cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1
protein, and show
elevated cholesterol synthetic rates, higher steady state levels of
cholesterol, and increased expression of
enzymes in the de novo
cholesterol biosynthetic pathways than the non-steroidogenic
prostate cancer cells. C81 cells also show decreased expression of the SXR
nuclear hormone receptor and a panel of directly regulated SXR target genes that govern
cholesterol efflux and
steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of
vitamin K-2, which is a potent endogenous
ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the
elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that coordinately promote both
cholesterol efflux and
androgen catabolism. Thus, loss of TERE1 during
tumor progression reduces K-2 levels resulting in reduced transcription of SXR target genes. We propose that TERE1 controls the CPRC phenotype by regulating the endogenous levels of
Vitamin K-2 and hence the transcriptional control of a suite of steroidogenic genes via the
SXR receptor. These data implicate the TERE1
protein as a previously unrecognized link affecting
cholesterol and
androgen accumulation that could govern acquisition of the CRPC phenotype.