RNA is a pro-apoptotic target of cisplatin in cancer cell lines and C. elegans - 22/03/24
Abstract |
Cisplatin not only targets DNA but also RNA. However, it is largely unknown whether platinated RNA (Pt-RNA) causes apoptosis and thus contributes to the cytotoxic effects of cisplatin. Consequently, cellular RNA was isolated from HepG2 and LS180 cells, exposed to cisplatin, and the resulting Pt-RNA (20 ng Pt/µg RNA) was transfected into these cancer cell lines or used to treat an apoptosis reporter Caenorhabditis elegans (C. elegans) strain (MD701, expressing CED-1::GFP). Cellular and molecular effects of Pt-RNA were evaluated by luminogenic caspase 3/7 assays, PCR array analysis, and fluorescence microscopy-based quantification of apoptosis in C. elegans gonads. Assuming RNA cross-linking (pseudo double-stranded RNA), the contribution of the Toll-like receptor 3 (TLR3, a sensor of double-stranded RNA) to apoptosis induction in cancer cell lines was investigated by pharmacological TLR3 inhibition and overexpression. In contrast to controls, Pt-RNA significantly enhanced apoptosis in C. elegans (2-fold) and in the cancer cell lines (2-fold to 4-fold). TLR3 overexpression significantly enhanced the pro-apoptotic effects of Pt-RNA in HepG2 cells. TLR3 inhibition reduced the pro-apoptotic effects of Pt-RNA and cisplatin, but not of paclitaxel (off-target control). Gene expression analysis showed that Pt-RNA (but not RNA) significantly enhanced the mRNA levels of nuclear factor kappa B subunit 2 and interleukin-8 in HepG2 cells, suggesting that Pt-RNA is a damage-associated molecular pattern that additionally causes pro-inflammatory responses. Together, this data suggests that not only DNA but also cellular RNA is a functionally relevant target of cisplatin, leading to pro-apoptotic and immunogenic effects.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Isolated cellular RNA was platinated with cisplatin (20 ng Pt/µg RNA). |
• | Platinated RNA causes apoptosis in cancer cell lines and C. elegans. |
• | The toll-like receptor 3 partly mediates this apoptosis induction. |
• | Platinated RNA enhances pro-inflammatory gene signatures. |
Abbreviations : C. elegans, DDTC, DsRNA, GFP, PolyI:C, Pt-RNA, TLR3
Keywords : Cisplatin, RNA platination, Apoptosis, Cancer cell lines, Caenorhabditis elegans, Toll-like receptor 3
Plan
Vol 173
Article 116450- avril 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?