RNA is a pro-apoptotic target of cisplatin in cancer cell lines and C. elegans
Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:173 |
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| Enthalten in: |
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie - 173(2024) vom: 19. März, Seite 116450 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rose, Fabian [VerfasserIn] |
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| Links: |
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| Themen: |
9007-49-2 |
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| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 27.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.biopha.2024.116450 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Caenorhabditis elegans | |
| 650 | 4 | |a Cancer cell lines | |
| 650 | 4 | |a Cisplatin | |
| 650 | 4 | |a RNA platination | |
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| 700 | 1 | |a Burhenne, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Weiss, Johanna |e verfasserin |4 aut | |
| 700 | 1 | |a Haefeli, Walter E |e verfasserin |4 aut | |
| 700 | 1 | |a Theile, Dirk |e verfasserin |4 aut | |
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