Notch and NOXA-related pathways in melanoma cells
Notch and NOXA-related pathways in melanoma cells
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DOI：
10.1111/j.1087-0024.2005.200404.x
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发表时间：
2005-11-01
影响因子：
--
通讯作者：
Qin, JZ
中科院分区：
文献类型：
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作者：
Nickoloff, BJ;Hendrix, MJC;Qin, JZ
Notch 受体介导的细胞内事件代表了一种古老的细胞信号系统，Notch 表达的改变与各种恶性肿瘤相关，在这些恶性肿瘤中，Notch 可能充当癌基因，或者不太常见地充当肿瘤抑制基因。 Notch 信号传导调节表皮中的细胞命运决定，包括影响干细胞动力学和皮肤细胞的生长/分化控制。由于越来越多的证据表明Notch信号网络在人类恶性肿瘤中失调，Notch受体已成为选择性杀死恶性细胞的有吸引力的靶标。与增殖的正常人类黑色素细胞相比，黑色素瘤细胞系的特点是激活的Notch-1受体水平显着增强。通过使用由三肽醛 N-benzyloxycarbonyl-Leu-Leu-NIe-CHO 组成的小分子 γ-分泌酶抑制剂 (GSI)，它可以阻断所有四种不同 Notch 受体的加工和激活，我们发现了黑色素瘤细胞中特定的凋亡脆弱性。 GSI 触发黑色素瘤细胞凋亡，但仅导致黑色素细胞 G2/M 期生长停滞，而不会导致随后的细胞死亡。此外，GSI 治疗在黑色素瘤细胞中诱导促凋亡 BH3 蛋白 NOXA，但在正常黑色素细胞中则不然。使用 GSI 诱导 NOXA 诱导克服了黑色素瘤细胞的凋亡抵抗，黑色素瘤细胞通常表达多种细胞生存蛋白，例如 Mcl-1、Bcl-2 和生存素。总而言之，这些结果强调了合成致死的概念，即暴露于 GSI 与过度表达激活的 Notch 受体的黑色素瘤细胞相结合，会产生致命的后果，选择性杀死黑色素瘤细胞，同时不伤害正常黑色素细胞。通过识别有助于黑色素瘤细胞转化的信号通路（例如 Notch 信号传导）和实现肿瘤选择性的抗癌药物（例如 GSI 诱导的 NOXA），该实验方法为皮肤肿瘤学的未来治疗策略提供了有用的框架。
Notch receptor-mediated intracellular events represent an ancient cell signaling system, and alterations in Notch expression are associated with various malignancies in which Notch may function as an oncogene or less commonly as a tumor suppressor. Notch signaling regulates cell fate decisions in the epidermis, including influencing stem cell dynamics and growth/differentiation control of cells in skin. Because of increasing evidence that the Notch signaling network is deregulated in human malignancies, Notch receptors have become attractive targets for selective killing of malignant cells. Compared with proliferating normal human melanocytes, melanoma cell lines are characterized by markedly enhanced levels of activated Notch-1 receptor. By using a small molecule gamma-secretase inhibitor (GSI) consisting of a tripeptide aldehyde, N-benzyloxycarbonyl-Leu-Leu-NIe-CHO, which can block processing and activation of all four different Notch receptors, we identified a specific apoptotic vulnerability in melanoma cells. GSI triggers apoptosis in melanoma cells, but only G2/M growth arrest in melanocytes without subsequent cell death. Moreover, GSI treatment induced a pro-apoptotic BH3-only protein, NOXA, in melanoma cells but not in normal melanocytes. The use of GSI to induce NOXA induction overcomes the apoptotic resistance of melanoma cells, which commonly express numerous cell survival proteins such as Mcl-1, Bcl-2, and survivin. Taken together, these results highlight the concept of synthetic lethality in which exposure to GSI, in combination with melanoma cells overexpressing activated Notch receptors, has lethal consequences, producing selective killing of melanoma cells, while sparing normal melanocytes. By identifying signaling pathways that contribute to the transformation of melanoma cells (e.g. Notch signaling), and anti-cancer agents that achieve tumor selectivity (e.g., GSI-induced NOXA), this experimental approach provides a useful framework for future therapeutic strategies in cutaneous oncology.