Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis
2018
Metastasis remains a leading
causeof
cancermortality 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 structureassociated with metastatic behaviors of cancer cells, as a phenotypic marker for a
high-content screenof 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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