Cyclic AMP Signaling as a Mediator of Vasculogenic Mimicry in Aggressive Human Melanoma Cells In vitro
Cyclic AMP Signaling as a Mediator of Vasculogenic Mimicry in Aggressive Human Melanoma Cells In vitro
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DOI：
10.1158/0008-5472.can-08-2391
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Verrando, Patrick
中科院分区：
文献类型：
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作者：
Lissitzky, Jean-Claude;Parriaux, Danielle;Verrando, Patrick
侵袭性黑色素瘤细胞可以参与称为血管生成拟态（VM）的过程，该过程反映了肿瘤细胞表达多能干细胞样表型的能力。黑色素瘤细胞的可塑性导致缺乏针对转移性肿瘤的有效治疗策略。本研究揭示了环腺苷酸在体外作为VM的介质。在葡萄膜和皮肤转移性侵袭性人黑色素瘤细胞中，毛喉素、二丁酰环腺苷酸或G蛋白偶联受体（GPCR）配体（如肾上腺素和血管活性肠肽）增加环腺苷酸可不同程度地抑制VM。虽然蛋白激酶A（PKA）的化学调节剂没有影响，一个特定的药理学激活剂的交换蛋白直接激活环磷酸腺苷（Epac）受损VM。Ras相关蛋白-1（Rapt）激活试验表明，环AMP升高剂诱导的PKA独立的Epac/Rap 1激活。药理学抑制细胞外信号调节激酶1/2（ERK 1/2）的活性废除VM。ERK 1/2的磷酸化被Forskolin抑制，但不被Epac/Rap 1信号转导、PKA调节或GPCR配体抑制。此外，毛喉素还抑制磷脂酰肌醇-3-激酶（PI 3 K）介导的蛋白激酶Akt的激活，如Ser 473磷酸化监测。Epac和GPCR配体的药理学活化轻微刺激Akt，这是VM调节的可能伴随过程。总的来说，这些数据表明，毛喉素强烈抑制VM通过PKA-非依赖性激活Epac/Rap 1，PKA-和Epac-非依赖性失活ERK 1/2和抑制PI 3 K/Akt。数据还表明，VM抑制GPCR配体主要涉及Epac/Rap 1激活的信号。因此，cAMP通过多种信号通路抑制VM。[Cancer Res 2009;69（3）：802-9]
Aggressive melanoma cells can engage in a process termed vasculogenic mimicry (VM) that reflects the ability of tumor cells to express a multipotent, stem cell-like phenotype. Melanoma cell plasticity contributes to the lack of efficient therapeutic strategies targeting metastatic tumors. This study reveals cyclic AMP as a mediator of VM in vitro. In uveal and cutaneous metastatic aggressive human melanoma cells, an increase in cyclic AMP by forskolin, dibutyryl cyclic AMP, or G protein-coupled receptor (GPCR) ligands such as adrenaline and vasoactive intestinal peptide inhibited VM to different extents. Although chemical modulators of protein kinase A (PKA) had no effect, a specific pharmacologic activator of Exchange protein directly activated by cyclic AMP (Epac) impaired VM. Ras-associated protein-1 (Rapt) activation assays revealed that cyclic AMP-elevating agents induce a PKA-independent activation of Epac/Rap1. Pharmacologic inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity abolished VM. Phosphorylation of ERK1/2 was PKA-independently inhibited by forskolin but not inhibited by Epac/Rap1 signaling, PKA modulation, or GPCR ligands. Furthermore, the forskolin also inhibited phosphatidyl inositol-3-kinase (PI3K)-mediated activation of protein kinase Akt, as monitored by Ser473 phosphorylation. The pharmacologic activation of Epac and GPCR ligands slightly stimulated Akt, a likely concomitant process of VM modulation. Collectively, these data show that forskolin strongly inhibits VM through PKA-independent activation of Epac/Rap1, PKA-, and Epac-independent inactivation of ERK1/2 and inhibition of PI3K/Akt. The data also show that VM inhibition by GPCR ligands involves mainly the Epac/Rap1-activated signal. Thus cyclic AMP inhibits VM through multiple signaling pathways. [Cancer Res 2009;69(3):802-9]