4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone inhibits MCPyV T antigen expression in Merkel cell carcinoma independent of Aurora kinase A
Please always quote using this URN: urn:nbn:de:bvb:20-opus-313547
- Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV), and MCPyV-positive tumor cells depend on expression of the virus-encoded T antigens (TA). Here, we identify 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone (PHT) — a reported inhibitor of Aurora kinase A — as a compound inhibiting growth of MCC cells by repressing noncoding control region (NCCR)-controlled TA transcription. Surprisingly, we find that TA repression is not caused by inhibition of Aurora kinase A. However, we demonstrate thatMerkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV), and MCPyV-positive tumor cells depend on expression of the virus-encoded T antigens (TA). Here, we identify 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone (PHT) — a reported inhibitor of Aurora kinase A — as a compound inhibiting growth of MCC cells by repressing noncoding control region (NCCR)-controlled TA transcription. Surprisingly, we find that TA repression is not caused by inhibition of Aurora kinase A. However, we demonstrate that β-catenin — a transcription factor repressed by active glycogen synthase kinase 3 (GSK3) — is activated by PHT, suggesting that PHT bears a hitherto unreported inhibitory activity against GSK3, a kinase known to function in promoting TA transcription. Indeed, applying an in vitro kinase assay, we demonstrate that PHT directly targets GSK3. Finally, we demonstrate that PHT exhibits in vivo antitumor activity in an MCC xenograft mouse model, suggesting a potential use in future therapeutic settings for MCC.…
Author: | Roland Houben, Pamela Alimova, Bhavishya Sarma, Sonja Hesbacher, Carolin Schulte, Eva-Maria Sarosi, Christian Adam, Thibault Kervarrec, David Schrama |
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URN: | urn:nbn:de:bvb:20-opus-313547 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie |
Language: | English |
Parent Title (English): | Cancers |
ISSN: | 2072-6694 |
Year of Completion: | 2023 |
Volume: | 15 |
Issue: | 9 |
Article Number: | 2542 |
Source: | Cancers (2023) 15:9, 2542. https://doi.org/10.3390/cancers15092542 |
DOI: | https://doi.org/10.3390/cancers15092542 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | GSK3; Merkel cell carcinoma; glycogen synthase kinase 3; large T antigen; phthalazinone pyrazole; polyomavirus |
Release Date: | 2024/01/17 |
Date of first Publication: | 2023/04/28 |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |