Stabilization of G-Quadruplexes Modulates the Expression of DNA Damage and Unfolded Protein Response Genes in Canine Lymphoma/Leukemia Cells

TL;DR

Stabilizing G-quadruplex structures in dog cancer cells affects genes involved in DNA damage and protein stress, suggesting a new approach for treating canine lymphoma.

Contribution

This study demonstrates that G-quadruplex stabilization modulates DNA damage and UPR gene expression in canine cancer cells.

Findings

PhenDC3 treatment downregulated DDR and UPR genes in CLBL-1 and CLB70 cells.

PhenDC3 upregulated DDR genes like PARP1 in GL-1 cells.

G4 stabilization enriched DNA replication and pyrimidine metabolism pathways in GL-1 cells.

Abstract

G-quadruplexes have been identified as a promising anti-cancer target because of their ability to modulate the stability of mRNAs encoding oncogenes, tumor suppressor genes, and other potential therapeutic targets. Deregulation of DNA damage and Unfolded Protein Response pathways in cancer cells may create vulnerabilities that can be exploited therapeutically. Previous studies have shown variations in the relative expression of DDR and UPR components in canine lymphoma and leukemia cell lines CLBL-1, CLB70, and GL-1. In the present study, we report the presence of G-quadruplex structures in these canine cell lines. Downregulation of the expression of DDR and UPR components at the mRNA level was observed in the CLBL-1 and CLB70 cell lines after stabilization of G4 structures using the ligand PhenDC3. In contrast, in GL-1 cells, important components of the DDR pathway, such as PARP1, GADD45A, and PIK3CB were upregulated in response to PhenDC3 treatment. Downregulation of DDIT4 mRNA expression, which encodes an important UPR component, was detected in the CLBL-1 and GL-1 cell lines after PhenDC3 exposure. These results suggest that G4 structures can be used to manipulate the expression of potential targets to treat lymphoma in dogs. A substantial enrichment of DNA replication and pyrimidine metabolism pathways was found in the GL-1 cell line after G4 stabilization. This finding suggests that PhenDC3 may induce DNA replication stress in this cell line. Collectively, these results support the feasibility of employing canine cancer cells as a model system to investigate the role of G-quadruplex structures in cancer.

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