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Sci Transl Med. 2018 May 16;10(441). pii: eaap8307. doi: 10.1126/scitranslmed.aap8307.

Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis.

Author information

1
Specialized Chemistry Center, The University of Kansas, Lawrence, KS 66047, USA.
2
Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA.
3
NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA.
4
Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
5
Center for Developmental Therapeutics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL 60208, USA.
6
Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
7
Departments of Molecular Biophysics and Biochemistry, Genetics, and Therapeutic Radiology, Yale University and Yale School of Medicine, New Haven, CT 06520, USA.
8
Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
9
Center for Advanced Preclinical Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Fort Detrick, Frederick, MD 21702, USA.
10
Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
11
Electron Microscope Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.
12
Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
13
Department of Human Genetics, Cancer Biology Graduate Program, Emory University School of Medicine, Atlanta, GA 30322, USA.
14
Thoracic and Gastrointestinal Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. s-huang2@northwestern.edu maruganj@mail.nih.gov rudloffu@mail.nih.gov.
15
NIH (National Institutes of Health) Chemical Genomics Center, National Center for Advancing Translational Sciences, NIH, Rockville, MD, 20850, USA. s-huang2@northwestern.edu maruganj@mail.nih.gov rudloffu@mail.nih.gov.
16
Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA. s-huang2@northwestern.edu maruganj@mail.nih.gov rudloffu@mail.nih.gov.

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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