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
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
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DOI：
10.3892/ijo.2013.1985
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发表时间：
2013-08-01
影响因子：
5.2
通讯作者：
Malkowicz, S. Bruce
中科院分区：
文献类型：
--
作者：
Fredericks, William J.;Yin, Hankun;Malkowicz, S. Bruce
目前对TERE 1（UBIAD 1）蛋白的研究强调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，TERE 1的深远影响涉及其异戊烯基转移酶活性，用于合成生物活性醌、甲萘醌和辅酶Q10。甲萘醌（又名维生素K-2）具有多种作用：作为线粒体电子传递的载体，作为SXR核激素受体活化的配体，作为氧化还原调节剂，以及作为细胞靶点的烷化剂。我们最初将TERE 1（UBIAD 1）蛋白描述为一种肿瘤抑制因子，其基础是在泌尿系癌症标本中表达减少以及异位表达后抑制肿瘤细胞系/异种移植物的生长。为了将TERE 1蛋白的这种潜在肿瘤抑制作用扩展到肾细胞癌（RCC），我们将TERE 1免疫组织化学应用于28个RCC病变的TMA组，并确定在57%的RCC病变中，TERE 1表达减少（36%）或缺失（21%）。在一组RCC细胞系中，异位TERE 1表达导致Caki-1和Caki-2细胞系生长减少80%，集落形成显著减少，并且半胱天冬酶3/7活性增加。此外，TERE 1表达增加线粒体耗氧和产氢，氧化应激和NO的产生。基于RCC的胆固醇升高和代谢表型改变，我们还研究了TERE 1和相互作用蛋白TBL 2对细胞胆固醇的影响。在Caki-1、Caki-2和HEK 293细胞中的异位TERE 1或TBL 2表达使胆固醇降低高达40%。RT-PCR分析确定TERE 1激活了几个已知调节脂质代谢的SXR靶点，这与基于其在甲基萘醌合成中的作用的预测一致。TERE 1的缺失可能通过ROS/RNS和SXR信号从胆固醇升高引起的细胞凋亡中解偶联而导致与RCC进展相关的脂质代谢表型改变。
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.