Academic Journal
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
| العنوان: | 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 |
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| المؤلفون: | Houben, Roland, Alimova, Pamela, Sarma, Bhavishya, Hesbacher, Sonja, Schulte, Carolin, Sarosi, Eva-Maria, Adam, Christian, Kervarrec, Thibault, Schrama, David |
| المساهمون: | University Hospital of Würzburg, Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) |
| المصدر: | ISSN: 2072-6694. |
| بيانات النشر: | HAL CCSD MDPI |
| سنة النشر: | 2023 |
| المجموعة: | Université François-Rabelais de Tours: HAL |
| مصطلحات موضوعية: | polyomavirus, large T antigen, phthalazinone pyrazole, glycogen synthase kinase 3, GSK3, Merkel cell carcinoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology |
| الوصف: | International audience ; Simple Summary: Treatment of Merkel cell carcinoma-a deadly skin cancer frequently caused by the Merkel cell polyomavirus-still poses challenges. Since the tumor cells depend on expression of viral oncogenes-named T antigens-targeting the expression of these T antigens appears as a potential therapeutic strategy. Therefore, we screened a kinase inhibitor library for compounds repressing growth of Merkel cell carcinoma cells specifically by inhibiting expression of these viral proteins and identified a compound previously described as an inhibitor of Aurora kinase A (AURKA). However, we provide evidence that the T-antigen repressing effect is not related to inhibition of AURKA but probably to a hitherto unknown GSK3-inhibitory activity of the compound, whose potential use a therapeutic is demonstrated in immunocompromised mice transplanted with human MCC.Abstract: 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 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/37174007; hal-04167787; https://hal.inrae.fr/hal-04167787; https://hal.inrae.fr/hal-04167787/document; https://hal.inrae.fr/hal-04167787/file/2023_Houben_cancers_vol-15_art-02542-v3.pdf; PUBMED: 37174007; WOS: 000987080100001 |
| DOI: | 10.3390/cancers15092542 |
| الاتاحة: | https://hal.inrae.fr/hal-04167787 https://hal.inrae.fr/hal-04167787/document https://hal.inrae.fr/hal-04167787/file/2023_Houben_cancers_vol-15_art-02542-v3.pdf https://doi.org/10.3390/cancers15092542 |
| Rights: | http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.1D51CC82 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3390/cancers15092542 |
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