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Exon-skipping antisense oligonucleotides targeting SUMO1 and SUMO2 demonstrate chemosensitizing effects in NSCLC
Andrea Garcia-Morin1, Rebeca Orozco-Sepulveda1, Yesenia Juarez-Vargas1
1The University of Texas at El Paso.
Abstract:
Lung cancer remains a leading cause of cancer-related death, highlighting the urgent need for new treatment strategies. SUMOylation, a post-translational modification that regulates DNA repair, replication, and cell cycle progression, is often increased in cancers and is a promising therapeutic target. Previously, we identified alternative splicing events affecting the SUMO transcripts, resulting in variant mRNAs coding for both non-conjugatable (SUMO1α and SUMO2α) and conjugatable (SUMO3α) isoforms-potentially helping to regulate overall cellular SUMOylation. In this study, we investigated whether increasing the levels of the transcripts coding for the non-conjugatable isoforms could decrease SUMOylation and improve chemotherapy efficacy in non-small cell lung cancer (NSCLC). To test this, we designed two sets of exon-skipping morpholinos called SUM2IN and SUMO1IN, targeting the pre-mRNAs of SUMO2 and SUMO1, respectively, and tested them in A549 and HCC827 cell lines. While treatment with SUM2IN significantly increased SUMO2α mRNA and reduced overall SUMO1 and SUMO2 conjugation in all tested cell lines, SUM1IN affected the proportion of SUMO1 mRNA variants and overall SUMO conjugation in a cell-type-specific manner. Still, both SUM2IN and SUM1IN altered cell cycle progression, decreased cell growth, and enhanced the cytotoxic effects of cisplatin and etoposide in A549 and HCC827 cells, while having a notably smaller impact on these parameters in the non-malignant lung fibroblast cell line HEL-299. Therefore, SUM2IN and SUM1IN display chemosensitizing activity against NSCLC and provide a strong foundation for developing SUMO-targeted chemosensitizers for NSCLC and other aggressive human cancers.
Insights
New strategies targeting SUMOylation in non-small cell lung cancer (NSCLC) show promise. Researchers developed compounds that reduce SUMOylation, enhancing chemotherapy effectiveness against lung cancer cells.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Lung cancer necessitates novel therapeutic strategies due to its high mortality rate.
- SUMOylation, a key regulator of DNA repair and cell cycle, is frequently elevated in cancers, presenting a potential therapeutic target.
- Alternative splicing of SUMO transcripts generates isoforms that may modulate cellular SUMOylation levels.
Purpose of the Study:
- To investigate if increasing non-conjugatable SUMO isoforms can reduce SUMOylation and improve chemotherapy efficacy in non-small cell lung cancer (NSCLC).
Main Methods:
- Development and application of exon-skipping morpholinos (SUM2IN and SUMO1IN) targeting SUMO2 and SUMO1 pre-mRNAs, respectively.
- Testing in NSCLC cell lines (A549, HCC827) and a non-malignant lung fibroblast cell line (HEL-299).
- Analysis of SUMOylation levels, mRNA variant proportions, cell cycle progression, cell growth, and response to chemotherapy agents (cisplatin, etoposide).
Main Results:
- SUM2IN treatment increased SUMO2α mRNA and decreased overall SUMO1/SUMO2 conjugation in tested cell lines.
- SUM1IN modulated SUMO1 mRNA variants and conjugation in a cell-type-specific manner.
- Both SUM2IN and SUM1IN treatments altered cell cycle, reduced cell growth, and enhanced chemotherapy cytotoxicity in NSCLC cells, with minimal effects on normal lung fibroblasts.
Conclusions:
- SUM2IN and SUMO1IN exhibit chemosensitizing activity against NSCLC.
- These findings support the development of SUMO-targeted chemosensitizers for NSCLC and other aggressive cancers.
