1. Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis
- Author
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Zachary Knotts, Susan J. Baserga, Eric Chow, Dandan Li, Udo Rudloff, Samarjit Patnaik, Warren Chen, Charles Long, Frank J. Schoenen, Wei Zheng, Steve Titus, Ming Zhou, Zhaojing Meng, Tomas Vilimas, Yiping Wen, Lesley A. Mathews Griner, Irawati Kandela, Yansong Bian, Marzena Anna Lewandowska, Jinsol Kang, Helen Huang, Jamey Sultan, Christopher R. Dextras, Ojus Khanolkar, Noel Southall, Jeffrey Aubé, John Norton, G. Gary Sahagian, Marc Ferrer, Esthermanya Goldberg, Ali Shilatifard, Kevin J. Frankowski, Min Fang, Katherine I. Farley, Sui Huang, Chen Wang, Yaroslav Teper, Romi Xi, Coral Feldman, Humair S. Quadri, Wei Sun, Juan J. Marugan, Kunio Nagashima, Andrew P. Mazar, Deqing Hu, Hyerim Kim, Astin Powers, and Serguei Kozlov
- Subjects
0301 basic medicine ,Male ,Transcription, Genetic ,EEF1A2 ,Biology ,DNA, Ribosomal ,Article ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Peptide Elongation Factor 1 ,Transcription (biology) ,RNA Polymerase I ,RNA polymerase ,Cell Line, Tumor ,medicine ,RNA Precursors ,Animals ,Humans ,Neoplasm Invasiveness ,Pyrroles ,Neoplasm Metastasis ,Promoter Regions, Genetic ,Cell Proliferation ,Perinucleolar compartment ,General Medicine ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,In vitro ,Chromatin ,Pancreatic Neoplasms ,030104 developmental biology ,Pyrimidines ,chemistry ,Cell culture ,Cancer cell ,Cancer research ,Cell Nucleolus - Abstract
Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.
- Published
- 2018