Notch1 is an effector of Akt and hypoxia in melanoma development
Notch1 is an effector of Akt and hypoxia in melanoma development
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DOI：
10.1172/jci36157
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发表时间：
2008-11-01
影响因子：
15.9
通讯作者：
Powell, Marianne Broome
中科院分区：
文献类型：
--
作者：
Bedogni, Barbara;Warneke, James A.;Powell, Marianne Broome
黑色素瘤是一种侵袭性很强的肿瘤，对大多数常规疗法都有抗药性。这些肿瘤是由改变的细胞内肿瘤抑制因子和癌基因与发生这些变化的微环境相互作用引起的。我们之前已经证明，生理性皮肤缺氧与Akt激活一起促进黑色素瘤的形成。我们发现Notch1信号在人类黑色素瘤样本和细胞系中升高，Akt和缺氧在体外转化黑色素细胞是必需的。Notch 1通过维持细胞增殖和保护细胞免受应激诱导的细胞死亡，促进了异种移植物模型中黑色素瘤的发展。过度激活的PI3K/Akt信号通过NF-kappa B活性导致Notch1的上调，而通常在皮肤中发现的低氧含量通过稳定HIF-1 α增加了Notch1的mRNA和蛋白水平。综上所述，这些发现表明Notch1在黑色素瘤的发展过程中是Akt和缺氧的关键效应因子，并确定了Notch信号通路作为黑色素瘤治疗的潜在治疗靶点。
Melanomas are highly aggressive neoplasms resistant to most conventional therapies. These tumors result from the interaction of altered intracellular tumor suppressors and oncogenes with the microenvironment in which these changes occur. We previously demonstrated that physiologic skin hypoxia contributes to melanomagenesis in conjunction with Akt activation. Here we show that Notch1 signaling is elevated in human melanoma samples and cell lines and is required for Akt and hypoxia to transform melanocytes in vitro. Notch 1 facilitated melanoma development in a xenograft model by maintaining cell proliferation and by protecting cells from stress-induced cell death. Hyperactivated PI3K/Akt signaling led to upregulation of Notch1 through NF-kappa B activity, while the low oxygen content normally found in skin increased mRNA and protein levels of Notch1 via stabilization of HIF-1 alpha. Taken together, these findings demonstrate that Notch1 is a key effector of both Akt and hypoxia in melanoma development and identify the Notch signaling pathway as a potential therapeutic target in melanoma treatment.