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Reduced Arginyltransferase 1 is a driver and a potential prognostic indicator of prostate cancer metastasis

Oncogene volume 38, pages 838–851 (2019)Cite this article

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Abstract

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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Acknowledgements

Cell sorting was performed in the core facility of Sylvester Comprehensive Cancer Center. Ex vivo imaging was performed in the small animal imaging facility at the University of Miami Miller School of medicine. Gamma irradiation was performed in the Radiation Control core facility at the University of Miami Miller School of medicine. Immunostaining of tumor array samples was performed in the histology core facility in the Hussman Institute for Human Genomics at the University of Miami Miller School of medicine. Dr. Priyamvada Rai (University of Miami) provided critical reading for the manuscript. Dr. Yuanfang Guan (University of Michigan) provided technical consultations for the analysis related to Ate1 mRNA levels. The research presented in this article is funded in part by these grants: DoD (CDMRP), Idea Award, PC140622; DoD (CDMRP), Exploratory grant, PC141013; and NIGMS (NIH), R01GM107333.

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  1. Akhilesh Kumar

    Present address: Department of Botany, Banaras Hindu University, Varanasi, 221005, India

Authors and Affiliations

  1. Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, USA

    Michael D. Birnbaum, Ning Zhao, Balaji T. Moorthy, Devang M. Patel, Laine Heidman, Akhilesh Kumar, William M. Morgan, Kerry L. Burnstein & Fangliang Zhang

  2. Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    Oleksandr N. Kryvenko, Isildinha M. Reis, Xi Chen, Mark L. Gonzalgo, Merce Jorda, Kerry L. Burnstein & Fangliang Zhang

  3. Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA

    Oleksandr N. Kryvenko & Merce Jorda

  4. Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA

    Oleksandr N. Kryvenko & Mark L. Gonzalgo

  5. Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

    Yuguang Ban, Isildinha M. Reis & Xi Chen

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  1. Michael D. Birnbaum
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Correspondence to Fangliang Zhang.

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Birnbaum, M.D., Zhao, N., Moorthy, B.T. et al. Reduced Arginyltransferase 1 is a driver and a potential prognostic indicator of prostate cancer metastasis. Oncogene 38, 838–851 (2019). https://doi.org/10.1038/s41388-018-0462-2

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