Division of Urology, Department of Surgery, University of Pennsylvania and Veterans Affairs Medical Center Philadelphia, Philadelphia, PA 19104, USA.
Int J Oncol. 2013 Aug;43(2):638-52. doi: 10.3892/ijo.2013.1985. Epub 2013 Jun 12.
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.
当前对 TERE1（UBIAD1）蛋白的研究强调了其对细胞的多因素影响，部分原因是其广泛的亚细胞分布到线粒体、内质网和高尔基体。然而，TERE1 的深远影响与其作为生物活性醌类物质menaquinone 和 COQ10 合成的prenyltransferase 活性有关。menaquinone（又名维生素 K-2）具有多种作用：作为线粒体电子传递中的载体，作为 SXR 核激素受体激活的配体，作为氧化还原调节剂，以及作为细胞靶标的烷基化剂。我们最初根据泌尿癌症标本中表达减少以及异位表达抑制肿瘤细胞系/异种移植物生长的情况，将 TERE1（UBIAD1）蛋白描述为肿瘤抑制因子。为了将 TERE1 蛋白的这种潜在肿瘤抑制作用扩展到肾细胞癌（RCC），我们应用 TERE1 免疫组化分析了 28 例 RCC 病变的 TMA 面板，并确定在 57%的 RCC 病变中，TERE1 表达减少（36%）或缺失（21%）。异位 TERE1 表达导致 Caki-1 和 Caki-2 细胞系的生长减少 80%，显著减少集落形成，并增加了一组 RCC 细胞系中的 caspase 3/7 活性。此外，TERE1 表达增加了线粒体耗氧量和产氢、氧化应激和 NO 产生。基于 RCC 的升高胆固醇和改变的代谢表型，我们还检查了 TERE1 和相互作用蛋白 TBL2 对细胞胆固醇的影响。在 Caki-1、Caki-2 和 HEK 293 细胞中异位表达 TERE1 或 TBL2 可使胆固醇减少多达 40%。RT-PCR 分析确定 TERE1 激活了几种已知调节脂质代谢的 SXR 靶标，这与基于其在menaquinone 合成中的作用的预测一致。TERE1 的缺失可能通过升高胆固醇使 ROS/RNS 和 SXR 信号与细胞凋亡脱偶联，导致与 RCC 进展相关的改变的脂质代谢表型。
