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

  • Authors:
    • William J. Fredericks
    • Hankun Yin
    • Priti Lal
    • Raghunath Puthiyaveettil
    • Stephen B. Malkowicz
    • Nathaniel J. Fredericks
    • John Tomaszewski
    • Frank J. Rauscher
    • S. Bruce Malkowicz
  • View Affiliations

  • Published online on: June 12, 2013     https://doi.org/10.3892/ijo.2013.1985
  • Pages: 638-652
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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.
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August 2013
Volume 43 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Fredericks WJ, Yin H, Lal P, Puthiyaveettil R, Malkowicz SB, Fredericks NJ, Tomaszewski J, Rauscher FJ and Malkowicz SB: 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. Int J Oncol 43: 638-652, 2013
APA
Fredericks, W.J., Yin, H., Lal, P., Puthiyaveettil, R., Malkowicz, S.B., Fredericks, N.J. ... Malkowicz, S.B. (2013). 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. International Journal of Oncology, 43, 638-652. https://doi.org/10.3892/ijo.2013.1985
MLA
Fredericks, W. J., Yin, H., Lal, P., Puthiyaveettil, R., Malkowicz, S. B., Fredericks, N. J., Tomaszewski, J., Rauscher , F. J., Malkowicz, S. B."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". International Journal of Oncology 43.2 (2013): 638-652.
Chicago
Fredericks, W. J., Yin, H., Lal, P., Puthiyaveettil, R., Malkowicz, S. B., Fredericks, N. J., Tomaszewski, J., Rauscher , F. J., Malkowicz, S. B."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". International Journal of Oncology 43, no. 2 (2013): 638-652. https://doi.org/10.3892/ijo.2013.1985