Reduced Arginyltransferase 1 is a driver and a potential prognostic indicator of prostate cancer metastasis.
Reduced Arginyltransferase 1 is a driver and a potential prognostic indicator of prostate cancer metastasis.
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DOI：
10.1038/s41388-018-0462-2
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发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Birnbaum MD;Zhao N;Moorthy BT;Patel DM;Kryvenko ON;Heidman L;Kumar A;Morgan WM;Ban Y;Reis IM;Chen X;Gonzalgo ML;Jorda M;Burnstein KL;Zhang F
大多数前列腺癌病例长期处于惰性状态，但转移进展会迅速恶化预后并导致死亡。然而，人们对促进前列腺癌转移的因素知之甚少，而且缺乏有效的预后指标，这使得管理治疗或监测的选择变得非常困难。精氨酸基转移酶1(ATE1)是介导蛋白质翻译后精氨酸化的酶，最近被认为是影响应激反应、细胞周期检查点和细胞迁移/黏附等多种癌症相关途径的主要调节因子。然而，ATE1在癌症中的确切作用仍不清楚。在本研究中，我们发现前列腺癌转移的发生与原发灶中Ate1蛋白和mRNA的水平呈负相关。我们还发现，转移性前列腺癌细胞系与非转移性细胞系相比，ATE1蛋白水平降低，并且ATE1基因的缺失会促使前列腺癌细胞向更具侵袭性的转移表型转变，而不会影响增殖率。此外，我们还证明了慢性应激可以导致ATE1的减少，而shRNA减少的ATE1增加了细胞对应激的抵抗力，并驱动了自发的和应激诱导的基因组突变。最后，通过使用前列腺正交性异种移植小鼠模型，我们发现ATE1的减少足以增强体内前列腺癌PC-3细胞的转移表型。我们的研究揭示了ATE1在抑制前列腺癌转移中的新作用，这对于建立前列腺癌转移指标以及寻找潜在的预防前列腺癌转移的治疗方法具有深远的意义。
Most prostate cancer cases remain indolent for long periods of time, but metastatic progression quickly worsens the prognosis and leads to mortality. However, little is known about what promotes the metastasis of prostate cancer and there is a lack of effective prognostic indicators, making it immensely difficult to manage options for treatment or surveillance. Arginyltransferase 1 (Ate1) is the enzyme mediating post-translational protein arginylation, which has recently been identified as a master regulator affecting many cancer-relevant pathways including stress response, cell cycle checkpoints, and cell migration/adhesion. However, the precise role of Ate1 in cancer remains unknown. In this study, we found the occurrence of metastasis of prostate cancer is inversely correlated with the levels of Ate1 protein and mRNA in the primary tumor. We also found that metastatic prostate cancer cell lines have a reduced level of Ate1 protein compared to non-metastatic cell lines, and that a depletion of Ate1 drives prostate cancer cells towards more aggressive pro-metastatic phenotypes without affecting proliferation rates. Furthermore, we demonstrated that a reduction of Ate1 can result from chronic stress, and that shRNA-reduced Ate1 increases cellular resistance to stress, and drives spontaneous and stress-induced genomic mutations. Finally, by using a prostate orthotropic xenograft mouse model, we found that a reduction of Ate1 was sufficient to enhance the metastatic phenotypes of prostate cancer cell line PC-3 in vivo. Our study revealed a novel role of Ate1 in suppressing prostate cancer metastasis, which has a profound significance for establishing metastatic indicators for prostate cancer, and for finding potential treatments to prevent its metastasis.
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影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
影响因子：
8
作者：
通讯作者：
--
影响因子：
8
作者：
Rai R;Zhang F;Colavita K;Leu NA;Kurosaka S;Kumar A;Birnbaum MD;Győrffy B;Dong DW;Shtutman M;Kashina A
通讯作者：
Kashina A
影响因子：
8
作者：
Rice MA;Ishteiwy RA;Magani F;Udayakumar T;Reiner T;Yates TJ;Miller P;Perez-Stable C;Rai P;Verdun R;Dykxhoorn DM;Burnstein KL
通讯作者：
Burnstein KL
影响因子：
11.2
作者：
Kumar, Binod;Koul, Sweaty;Koul, Hari K.
通讯作者：
Koul, Hari K.