Reciprocal regulation of MelCAM and AKT in human melanoma
Reciprocal regulation of MelCAM and AKT in human melanoma
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DOI：
10.1038/sj.onc.1206819
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发表时间：
2003-10-09
期刊：
影响因子：
8
通讯作者：
Herlyn, M
中科院分区：
文献类型：
--
作者：
Li, G;Kalabis, J;Herlyn, M
侵袭/转移相关黑色素瘤细胞粘附分子（MelCAM）表达的改变与人黑色素瘤恶性程度的获得密切相关。然而，关于调节MelCAM的表达和功能的分子和生化机制或其下游信号转导知之甚少。在这项研究中，我们发现AKT和MelCAM之间存在相互调节回路。药理学抑制人黑素瘤细胞系中的AKT实质上降低了MelCAM的表达。组成型活性AKT的过表达上调MelCAM在黑色素瘤细胞系中的水平，而显性负PI-3激酶的表达下调MelCAM。另一方面，MelCAM的过表达激活了内源性AKT并抑制了黑色素瘤细胞中的促凋亡蛋白BAD，从而增加了应激条件下的存活率。在大多数黑色素瘤细胞系和不同进展阶段的肿瘤样品中观察到AKT的组成性激活。这些数据将AKT激活与MelCAM表达联系起来，并暗示干预MelCAM-AKT信号传导轴是黑色素瘤中潜在的治疗方法。
Alteration in the expression of invasion/ metastasis-related melanoma cell adhesion molecule (MelCAM) is strongly associated with the acquisition of malignancy by human melanoma. However, little is known about the molecular and biochemical mechanisms that regulate the expression and function of MelCAM, or its downstream signaling transduction. In this study, we show that there is a reciprocal regulation loop between AKT and MelCAM. Pharmacological inhibition of AKT in human melanoma cell lines substantially reduced the expression of MelCAM. Overexpression of constitutively active AKT upregulated the levels of MelCAM in melanoma cell lines, whereas expression of a dominant-negative PI-3 kinase downregulated MelCAM. On the other hand, overexpression of MelCAM activated endogenous AKT and inhibited proapoptotic protein BAD in melanoma cells, leading to increased survival under stress conditions. Constitutive activation of AKT was observed in most melanoma cell lines and tumor samples of different progression stages. These data link AKT activation with MelCAM expression, and implicate that intervention of MelCAM-AKT signaling axis in melanoma is a potential therapeutical approach.