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 SultanZhaojing 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

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Scopus citations

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 perinuclear 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.

Original languageEnglish (US)
Article numbereaap8307
JournalScience translational medicine
Volume10
Issue number441
DOIs
StatePublished - May 16 2018

ASJC Scopus subject areas

  • Medicine(all)

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    Frankowski, K. J., Wang, C., Patnaik, S., Schoenen, F. J., Southall, N., Li, D., Teper, Y., Sun, W., Kandela, I., Hu, D., Dextras, C., Knotts, Z., Bian, Y., Norton, J., Titus, S., Lewandowska, M. A., Wen, Y., Farley, K. I., Griner, L. M., ... Huang, S. (2018). Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis. Science translational medicine, 10(441), [eaap8307]. https://doi.org/10.1126/scitranslmed.aap8307