RNA is a pro-apoptotic target of cisplatin in cancer cell lines and C. elegans

• Verfasst von: Rose, Fabian [VerfasserIn]
• Verfasst von: Köberle, Beate [VerfasserIn]
• Verfasst von: Honnen, Sebastian Jakob [VerfasserIn]
• Verfasst von: Bay, Cindy [VerfasserIn]
• Verfasst von: Burhenne, Jürgen [VerfasserIn]
• Verfasst von: Weiß, Johanna [VerfasserIn]
• Verfasst von: Haefeli, Walter E. [VerfasserIn]
• Verfasst von: Theile, Dirk [VerfasserIn]
• Titel: RNA is a pro-apoptotic target of cisplatin in cancer cell lines and C. elegans
• Verf.angabe: Fabian Rose, Beate Köberle, Sebastian Honnen, Cindy Bay, Jürgen Burhenne, Johanna Weiss, Walter E. Haefeli, Dirk Theile
• E-Jahr: 2024
• Jahr: 18 March 2024
• Umfang: 10 S.
• Fussnoten: Gesehen am 14.11.2024
• Titel Quelle: Enthalten in: Biomedicine & pharmacotherapy
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1989
• Jahr Quelle: 2024
• Band/Heft Quelle: 173(2024), Artikel-ID 116450, Seite 116450-1-116450-10
• ISSN Quelle: 1950-6007
• DOI: doi:10.1016/j.biopha.2024.116450
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Apoptosis
• Sach-SW: Cancer cell lines
• Sach-SW: Cisplatin
• Sach-SW: RNA platination
• Sach-SW: Toll-like receptor 3
• K10plus-PPN: 190856783X

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 (20ng 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.