TY - JOUR
T1 - Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis
AU - Frankowski, Kevin J.
AU - Wang, Chen
AU - Patnaik, Samarjit
AU - Schoenen, Frank J.
AU - Southall, Noel
AU - Li, Dandan
AU - Teper, Yaroslav
AU - Sun, Wei
AU - Kandela, Irawati
AU - Hu, Deqing
AU - Dextras, Christopher
AU - Knotts, Zachary
AU - Bian, Yansong
AU - Norton, John
AU - Titus, Steve
AU - Lewandowska, Marzena A.
AU - Wen, Yiping
AU - Farley, Katherine I.
AU - Griner, Lesley Mathews
AU - Sultan, Jamey
AU - Meng, Zhaojing
AU - Zhou, Ming
AU - Vilimas, Tomas
AU - Powers, Astin S.
AU - Kozlov, Serguei
AU - Nagashima, Kunio
AU - Quadri, Humair S.
AU - Fang, Min
AU - Long, Charles
AU - Khanolkar, Ojus
AU - Chen, Warren
AU - Kang, Jinsol
AU - Huang, Helen
AU - Chow, Eric
AU - Goldberg, Esthermanya
AU - Feldman, Coral
AU - Xi, Romi
AU - Kim, Hye Rim
AU - Sahagian, Gary
AU - Baserga, Susan J.
AU - Mazar, Andrew
AU - Ferrer, Marc
AU - Zheng, Wei
AU - Shilatifard, Ali
AU - Aubé, Jeffrey
AU - Rudloff, Udo
AU - Marugan, Juan Jose
AU - Huang, Sui
N1 - Funding Information:
Acknowledgments: We would like to thank U. Kutay for the GFP-RPL29 cell line, M. S. Irwin for the HA-eEF1A1 and HA-eEF1A2 constructs, and S.-Y. Cheng for the cell lines. We thank the Center for Therapeutic Development, Genomic Core Facility, and Cell Imaging Facility of Northwestern University (NU) for the support of some of the work. The opinions expressed in this article are the authors’ own and do not reflect the view of the NIH, the Department of Health and Human Services, or the U.S. government. This study was supported by the intramural research program of the NIH (J.J.M., M. Ferrer, W.Z., and U.R.), including ZIA BC 011267 (to U.R.). Other support included NIHR01GM115710 (to S.B.); NIH F31DE026946 (to K.I.F.); NIH R01GM078555 (to S.H.); IDP, H, and V foundation funding through Robert H. Lurie Comprehensive Cancer Center at NU (to S.H.); donations from the Baskes family to the Robert H. Lurie Comprehensive Cancer Center, NU, from “Running for Rachel” to the National Cancer Institute (to U.R.); Cancer Center Support grant no. 2 P30 CA060553-19 (to A.P.M.); Robert H. Lurie Comprehensive Cancer Center–Translational Bridge Program Fellowship in Lymphoma Research (to D.H.); and Molecular Libraries Initiative funding to the University of Kansas Specialized Chemistry Center (U54HG005031) (to J.A.).
Funding Information:
Acknowledgments: We would like to thank U. Kutay for the GFP-RPL29 cell line, M. S. Irwin for the HA-eEF1A1 and HA-eEF1A2 constructs, and S.-Y. Cheng for the cell lines. We thank the Center for Therapeutic Development, Genomic Core Facility, and Cell Imaging Facility of Northwestern University (NU) for the support of some of the work. The opinions expressed in this article are the authors? own and do not reflect the view of the NIH, the Department of Health and Human Services, or the U.S. government. This study was supported by the intramural research program of the NIH (J.J.M., M. Ferrer, W.Z., and U.R.), including ZIA BC 011267 (to U.R.). Other support included NIHR01GM115710 (to S.B.); NIH F31DE026946 (to K.I.F.); NIH R01GM078555 (to S.H.); IDP, H, and V foundation funding through Robert H. Lurie Comprehensive Cancer Center at NU (to S.H.); donations from the Baskes family to the Robert H. Lurie Comprehensive Cancer Center, NU, from ?Running for Rachel? to the National Cancer Institute (to U.R.); Cancer Center Support grant no. 2 P30 CA060553-19 (to A.P.M.); Robert H. Lurie Comprehensive Cancer Center?Translational Bridge Program Fellowship in Lymphoma Research (to D.H.); and Molecular Libraries Initiative funding to the University of Kansas Specialized Chemistry Center (U54HG005031) (to J.A.).
Publisher Copyright:
Copyright © 2018 The Authors.
PY - 2018/5/16
Y1 - 2018/5/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047366817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047366817&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aap8307
DO - 10.1126/scitranslmed.aap8307
M3 - Article
C2 - 29769289
AN - SCOPUS:85047366817
SN - 1946-6234
VL - 10
JO - Science translational medicine
JF - Science translational medicine
IS - 441
M1 - eaap8307
ER -
