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Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis.


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.

SUBMITTER: Frankowski KJ 

PROVIDER: S-EPMC6176865 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis.

Frankowski Kevin J KJ   Wang Chen C   Patnaik Samarjit S   Schoenen Frank J FJ   Southall Noel N   Li Dandan D   Teper Yaroslav Y   Sun Wei W   Kandela Irawati I   Hu Deqing D   Dextras Christopher C   Knotts Zachary Z   Bian Yansong Y   Norton John J   Titus Steve S   Lewandowska Marzena A MA   Wen Yiping Y   Farley Katherine I KI   Griner Lesley Mathews LM   Sultan Jamey J   Meng Zhaojing Z   Zhou Ming M   Vilimas Tomas T   Powers Astin S AS   Kozlov Serguei S   Nagashima Kunio K   Quadri Humair S HS   Fang Min M   Long Charles C   Khanolkar Ojus O   Chen Warren W   Kang Jinsol J   Huang Helen H   Chow Eric E   Goldberg Esthermanya E   Feldman Coral C   Xi Romi R   Kim Hye Rim HR   Sahagian Gary G   Baserga Susan J SJ   Mazar Andrew A   Ferrer Marc M   Zheng Wei W   Shilatifard Ali A   Aubé Jeffrey J   Rudloff Udo U   Marugan Juan Jose JJ   Huang Sui S  

Science translational medicine 20180501 441


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 mu  ...[more]

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