The Nucleolin Antagonist N6L Inhibits LINE1 Retrotransposon Activity in Non-Small Cell Lung Carcinoma Cells
AuthorRamos, Kenneth S.
Tavera-Garcia, Marco A.
Reyes-Reyes, Elsa M.
AffiliationUniv Arizona, Coll Med, Dept Med, Div Pulm Allergy Crit Care & Sleep Med
Univ Arizona, Ctr Canc, Dept Cellular & Mol Med
MetadataShow full item record
PublisherIVYSPRING INT PUBL
CitationRamos KS, Moore S, Runge I, Tavera-Garcia MA, Cascone I, Courty J, Reyes-Reyes EM. The Nucleolin Antagonist N6L Inhibits LINE1 Retrotransposon Activity in Non-Small Cell Lung Carcinoma Cells. J Cancer 2020; 11(3):733-740. doi:10.7150/jca.37776. Available from http://www.jcancer.org/v11p0733.htm
JournalJOURNAL OF CANCER
RightsCopyright © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
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AbstractLung cancer is the most common cause of cancer death in the United States. The genome of non-small cell lung cancer (NSCLC), the most frequent lung cancer type, is strongly affected by Long Interspersed Nuclear Element (LINE1) insertions. Active LINE1s are repetitive DNA sequences that can amplify themselves in the genome utilizing a retrotransposition mechanism whereby LINE1 is copied via reverse transcription and inserted at target sites. ORF1p and ORF2p are LINE1 encoded proteins essential for LINE1 retrotransposition. LINE1s are silenced epigenetically in somatic tissues, and their reactivation has been associated with cancer pathogenesis. Here, we present evidence that nucleolin (NCL) regulates expression of LINE1-ORF1p (L1-ORF1p) in NSCLC cells. Genetic knockdown of NCL significantly inhibited expression of L1-ORF1p in various NSCLC cell lines. Treatment with the investigational NCL antagonist N6L ablated L1-ORF1p expression in all cell lines constitutively expressing L1-ORFp. N6L displayed a stronger antiproliferative activity in NSCLC tumor cell lines expressing the highest L1-ORF1p protein levels. Moreover, N6L treatment of nude mice bearing NSCLC tumor xenografts blocked L1-ORF1p expression and effectively inhibited tumor growth. These data indicate that L1-ORF1p expression is regulated by NCL and identify NCL as a novel promising target for pharmacological inhibition of LINE1.
NoteOpen access journal
VersionFinal published version
SponsorsAmerica Cancer Society [IRG-16-124-37]; University of Arizona Career Development Award; GURI Award; Agence National pour la RechercheFrench National Research Agency (ANR) [ANR-16 CE17-0023]
Except where otherwise noted, this item's license is described as Copyright © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).