ADP-ribosylation factor 6 regulates tumorigenic and invasive properties in vivo.
ADP-ribosylation factor 6 regulates tumorigenic and invasive properties in vivo.
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DOI：
10.1158/0008-5472.can-08-1301
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
D'Souza-Schorey C
中科院分区：
文献类型：
--
作者：
Muralidharan-Chari V;Hoover H;Clancy J;Schweitzer J;Suckow MA;Schroeder V;Castellino FJ;Schorey JS;D'Souza-Schorey C
这项研究表明，小GTP结合蛋白ADP-核糖基化因子6（ARF 6）是肿瘤生长和转移的重要调节因子。使用自发性黑色素瘤肿瘤生长测定和裸鼠实验转移测定，我们表明，持续激活的ARF 6减少肿瘤块的生长，但显着增强肿瘤细胞的侵袭能力。相反，与对照动物相比，注射表达显性抑制性ARF 6突变体的肿瘤细胞的小鼠表现出较低的侵袭和肺转移发生率和程度。对肿瘤生长的影响与细胞增殖能力降低相关，至少部分与缺陷性ARF 6循环诱导的有丝分裂进程改变有关。此外，ARF 6（GTP）和ARF 6（GDP）肿瘤外植体的继代培养细胞中的磷酸化ERK水平与侵袭能力相关。ARF 6诱导的细胞外信号调节激酶（ERK）信号传导导致Rac 1激活，以促进侵袭伪足形成和细胞侵袭。这些发现证明了ARF 6和ERK激活调节在协调黑色素瘤生长、侵袭和转移机制中的复杂作用。
This study shows that the small GTP-binding protein ADP-ribosylation factor 6 (ARF6) is an important regulator of tumor growth and metastasis. Using spontaneous melanoma tumor growth assays and experimental metastasis assays in nude mice, we show that sustained activation of ARF6 reduces tumor mass growth but significantly enhances the invasive capacity of tumor cells. In contrast, mice injected with tumor cells expressing a dominantly inhibitory ARF6 mutant exhibited a lower incidence and degree of invasion and lung metastasis compared with control animals. Effects on tumor growth correlate with reduced cell proliferation capacity and are linked at least in part to alterations in mitotic progression induced by defective ARF6 cycling. Furthermore, phospho-ERK levels in subcultured cells from ARF6(GTP) and ARF6(GDP) tumor explants correlate with invasive capacity. ARF6-induced extracellular signal-regulated kinase (ERK) signaling leads to Rac1 activation to promote invadopodia formation and cell invasion. These findings document an intricate role for ARF6 and the regulation of ERK activation in orchestrating mechanisms underlying melanoma growth, invasion, and metastases.