J Cancer 2020; 11(3):733-740. doi:10.7150/jca.37776

Research Paper

The Nucleolin Antagonist N6L Inhibits LINE1 Retrotransposon Activity in Non-Small Cell Lung Carcinoma Cells

Kenneth S. Ramos1,2, Sara Moore2, Isabel Runge2, Marco A. Tavera-Garcia2, Ilaria Cascone3, Jose Courty3, Elsa M. Reyes-Reyes2,4✉

1. Texas A&M University College of Medicine, Department of Medicine and Institute of Biosciences and Technology, Houston, Texas 77030, USA.
2. University of Arizona College of Medicine, Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Tucson, Arizona 85721.
3. University of Paris Est (UPEC), ERL-CNRS 9215, Laboratory of Growth, Reparation, and Tissue Regeneration (CRRET), UPEC, 94010 Créteil, France.
4. Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, AZ, 85721.

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Citation:
Ramos 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

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Abstract

Lung 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.

Keywords: Nucleolin, LINE1, NSCLC, and Lung cancer.