CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells
Uveal melanoma (UM) is among the most common primary intraocular neoplasms in adults, with limited therapeutic options for advanced/metastatic disease. Since UM is characterized by infrequent p53 mutation coupled with the overexpression of MDM4, a major negative regulator of p53, we aimed to investi...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/1/118 |
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| author | Keita Togashi Shuhei Suzuki Yuta Mitobe Yurika Nakagawa-Saito Asuka Sugai Senri Takenouchi Masahiko Sugimoto Chifumi Kitanaka Masashi Okada |
| author_facet | Keita Togashi Shuhei Suzuki Yuta Mitobe Yurika Nakagawa-Saito Asuka Sugai Senri Takenouchi Masahiko Sugimoto Chifumi Kitanaka Masashi Okada |
| author_sort | Keita Togashi |
| collection | DOAJ |
| description | Uveal melanoma (UM) is among the most common primary intraocular neoplasms in adults, with limited therapeutic options for advanced/metastatic disease. Since UM is characterized by infrequent p53 mutation coupled with the overexpression of MDM4, a major negative regulator of p53, we aimed to investigate in this study the effects on UM cells of CEP-1347, a novel MDM4 inhibitor with a known safety profile in humans. We also examined the impact of CEP-1347 on the protein kinase C (PKC) pathway, known to play a pivotal role in UM cell growth. High-grade UM cell lines were used to analyze the effects of genetic and pharmacological inhibition of MDM4 and PKC, respectively, as well as those of CEP-1347 treatment, on p53 expression and cell viability. The results showed that, at its clinically relevant concentrations, CEP-1347 reduced not only MDM4 expression but also PKC activity, activated the p53 pathway, and effectively inhibited the growth of UM cells. Importantly, whereas inhibition of either MDM4 expression or PKC activity alone failed to efficiently activate p53 and inhibit cell growth, inhibition of both resulted in effective activation of p53 and inhibition of cell growth. These data suggest that there exists a hitherto unrecognized interaction between MDM4 and PKC to inactivate the p53-dependent growth control in UM cells. CEP-1347, which dually targets MDM4 and PKC, could therefore be a promising therapeutic candidate in the treatment of UM. |
| first_indexed | 2024-03-08T15:10:05Z |
| format | Article |
| id | doaj.art-15a4185197b3476b90dcabaec52c6fba |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T15:10:05Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-15a4185197b3476b90dcabaec52c6fba2024-01-10T14:52:44ZengMDPI AGCancers2072-66942023-12-0116111810.3390/cancers16010118CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma CellsKeita Togashi0Shuhei Suzuki1Yuta Mitobe2Yurika Nakagawa-Saito3Asuka Sugai4Senri Takenouchi5Masahiko Sugimoto6Chifumi Kitanaka7Masashi Okada8Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanDepartment of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanDepartment of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanDepartment of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanDepartment of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanDepartment of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanDepartment of Ophthalmology and Visual Sciences, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanDepartment of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanDepartment of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, JapanUveal melanoma (UM) is among the most common primary intraocular neoplasms in adults, with limited therapeutic options for advanced/metastatic disease. Since UM is characterized by infrequent p53 mutation coupled with the overexpression of MDM4, a major negative regulator of p53, we aimed to investigate in this study the effects on UM cells of CEP-1347, a novel MDM4 inhibitor with a known safety profile in humans. We also examined the impact of CEP-1347 on the protein kinase C (PKC) pathway, known to play a pivotal role in UM cell growth. High-grade UM cell lines were used to analyze the effects of genetic and pharmacological inhibition of MDM4 and PKC, respectively, as well as those of CEP-1347 treatment, on p53 expression and cell viability. The results showed that, at its clinically relevant concentrations, CEP-1347 reduced not only MDM4 expression but also PKC activity, activated the p53 pathway, and effectively inhibited the growth of UM cells. Importantly, whereas inhibition of either MDM4 expression or PKC activity alone failed to efficiently activate p53 and inhibit cell growth, inhibition of both resulted in effective activation of p53 and inhibition of cell growth. These data suggest that there exists a hitherto unrecognized interaction between MDM4 and PKC to inactivate the p53-dependent growth control in UM cells. CEP-1347, which dually targets MDM4 and PKC, could therefore be a promising therapeutic candidate in the treatment of UM.https://www.mdpi.com/2072-6694/16/1/118intraocular malignancyMDMXKT7515choroidciliary bodyiris |
| spellingShingle | Keita Togashi Shuhei Suzuki Yuta Mitobe Yurika Nakagawa-Saito Asuka Sugai Senri Takenouchi Masahiko Sugimoto Chifumi Kitanaka Masashi Okada CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells Cancers intraocular malignancy MDMX KT7515 choroid ciliary body iris |
| title | CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells |
| title_full | CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells |
| title_fullStr | CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells |
| title_full_unstemmed | CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells |
| title_short | CEP-1347 Dually Targets MDM4 and PKC to Activate p53 and Inhibit the Growth of Uveal Melanoma Cells |
| title_sort | cep 1347 dually targets mdm4 and pkc to activate p53 and inhibit the growth of uveal melanoma cells |
| topic | intraocular malignancy MDMX KT7515 choroid ciliary body iris |
| url | https://www.mdpi.com/2072-6694/16/1/118 |
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