Togashi Keita, Suzuki Shuhei, Mitobe Yuta, Nakagawa-Saito Yurika, Sugai Asuka, Takenouchi Senri, Sugimoto Masahiko, Kitanaka Chifumi, Okada Masashi
Department of Molecular Cancer Science, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Department of Ophthalmology and Visual Sciences, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan.
Cancers (Basel). 2023 Dec 25;16(1):118. doi: 10.3390/cancers16010118.
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.
葡萄膜黑色素瘤（UM）是成人中最常见的原发性眼内肿瘤之一，对于晚期/转移性疾病，治疗选择有限。由于UM的特征是p53突变罕见，同时伴有p53的主要负调节因子MDM4的过表达，我们在本研究中旨在探究CEP - 1347对UM细胞的影响，CEP - 1347是一种新型MDM4抑制剂，在人体中具有已知的安全性。我们还研究了CEP - 1347对蛋白激酶C（PKC）通路的影响，已知该通路在UM细胞生长中起关键作用。分别使用高级别UM细胞系来分析MDM4和PKC的基因抑制和药理抑制以及CEP - 1347处理对p53表达和细胞活力的影响。结果表明，在其临床相关浓度下，CEP - 1347不仅降低了MDM4表达，还降低了PKC活性，激活了p53通路，并有效抑制了UM细胞的生长。重要的是，单独抑制MDM4表达或PKC活性均未能有效激活p53并抑制细胞生长，而两者同时抑制则导致p53有效激活和细胞生长抑制。这些数据表明，MDM4和PKC之间存在一种迄今未被认识的相互作用，可使UM细胞中p53依赖性生长控制失活。因此，双重靶向MDM4和PKC的CEP - 1347可能是治疗UM的有前景的候选药物。
