Ectopic expression of the TERE1 (UBIAD1) protein inhibits growth of renal clear cell carcinoma cells: Altered metabolic phenotype associated with reactive oxygen species, nitric oxide and SXR target genes involved in cholesterol and lipid metabolism

Abstract

Current studies of the TERE1 (UBIAD1) protein emphasize its multifactorial influence on the cell, in part due to its broad sub-cellular distribution to mitochondria, endoplasmic reticulum and golgi. However, the profound effects of TERE1 relate to its prenyltransferase activity for synthesis of the bioactive quinones menaquinone and COQ10. Menaquinone (aka, vitamin K-2) serves multiple roles: as a carrier in mitochondrial electron transport, as a ligand for SXR nuclear hormone receptor activation, as a redox modulator, and as an alkylator of cellular targets. We initially described the TERE1 (UBIAD1) protein as a tumor suppressor based upon reduced expression in urological cancer specimens and the inhibition of growth of tumor cell lines/xenografts upon ectopic expression. To extend this potential tumor suppressor role for the TERE1 protein to renal cell carcinoma (RCC), we applied TERE1 immunohistochemistry to a TMA panel of 28 RCC lesions and determined that in 57% of RCC lesions, TERE1 expression was reduced (36%) or absent (21%). Ectopic TERE1 expression caused an 80% decrease in growth of Caki-1 and Caki-2 cell lines, a significantly decreased colony formation, and increased caspase 3/7 activity in a panel of RCC cell lines. Furthermore, TERE1 expression increased mitochondrial oxygen consumption and hydrogen production, oxidative stress and NO production. Based on the elevated cholesterol and altered metabolic phenotype of RCC, we also examined the effects of TERE1 and the interacting protein TBL2 on cellular cholesterol. Ectopic TERE1 or TBL2 expression in Caki-1, Caki-2 and HEK 293 cells reduced cholesterol by up to 40%. RT-PCR analysis determined that TERE1 activated several SXR targets known to regulate lipid metabolism, consistent with predictions based on its role in menaquinone synthesis. Loss of TERE1 may contribute to the altered lipid metabolic phenotype associated with progression in RCC via an uncoupling of ROS/RNS and SXR signaling from apoptosis by elevation of cholesterol.

The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes

“…Our initial interest was precipitated by our earlier demonstration that TERE1 message was reduced in ~60% (18 of 30) of human prostate cancer specimens [29, 30]. We have also found similar TERE1 expression reduction in renal clear cell cancers, another example of a tumor with an elevated cholesterol phenotype and in bladder cancer [32, 33, 49]. With this prostate cancer study, our TERE1 immunohistochemical analysis found TERE1 staining was reduced or completely absent in over half of 50 primary and metastatic specimens.…”

Mitochondrial damage and cholesterol storage in human hepatocellular carcinoma cells with silencing of UBIAD1 gene expression

“…This is indirectly supported by studies demonstrating that the protein plays a tumor suppressor role in cholesterol-dependent bladder and prostate cancers [6], [11]. Multiple tumor cell lines with high levels of lipid accumulation also showed a loss of UBIAD1 expression, while UBIAD1 overexpression in these lines leads to a decrease in cholesterol, along with an abatement in tumor size and proliferation [6], [12]. Furthermore, Ubiad1 protein was identified as an interacting partner of cholesterol-transporting protein, apolipoprotein E [6], [13] as well as of HMGCR and SOAT1 enzymes catalyzing, respectively, cholesterol synthesis and storage [1].…”

Nitric oxide inhibits autophagy and promotes apoptosis in hepatocellular carcinoma

“…nNOS and eNOS are constitutively present in peripheral nerves and vascular endothelial cells, respectively, whereas iNOS is inducible, mainly in pathological conditions, by mesenchymal cells and parenchymal cells through the stimulation of endotoxins and cytokines. The expression of NOS has been detected in various cancers such as breast, bladder, stomach, prostate, lung, colon, pancreas and renal cancers . In liver cancer, the expression pattern of NOS remains unknown.…”