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Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis
Frankowski et al.
Frankowski et al.
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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.
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This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Translational Medicine on Vol 10, 16 may 2018, DOI: 10.1126/scitranslmed.aap8307.
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2018-05-16
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American Association for the Advancement of Science
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Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis.
Kevin J. Frankowski, Chen Wang, Samarjit Patnaik, Frank J. Schoenen, Noel Southall, Dandan Li, Yaroslav Teper, Wei Sun, Irawati Kandela, Deqing Hu, Christopher Dextras, Zachary Knotts, Yansong Bian, John Norton, Steve Titus, Marzena A. Lewandowska, Yiping Wen, Katherine I. Farley, Lesley Mathews Griner, Jamey Sultan, Zhaojing Meng, Ming Zhou, Tomas Vilimas, Astin S. Powers, Serguei Kozlov, Kunio Nagashima, Humair S. Quadri, Min Fang, Charles Long, Ojus Khanolkar, Warren Chen, Jinsol Kang, Helen Huang, Eric Chow, Esthermanya Goldberg, Coral Feldman, Romi Xi, Hye Rim Kim, Gary Sahagian, Susan J. Baserga, Andrew Mazar, Marc Ferrer, Wei Zheng, Ali Shilatifard, Jeffrey Aubé, Udo Rudloff, Juan Jose Marugan, Sui Huang
Sci Transl Med. 2018 May 16; 10(441): eaap8307. doi: 10.1126/scitranslmed.aap8307