Sorafenib inhibits cAMP-dependent ERK activation, cell proliferation, and in vitro cyst growth of human ADPKD cyst epithelial cells.
Sorafenib inhibits cAMP-dependent ERK activation, cell proliferation, and in vitro cyst growth of human ADPKD cyst epithelial cells.
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DOI：
10.1152/ajprenal.00387.2010
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发表时间：
2010-11
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影响因子：
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通讯作者：
Tamio Yamaguchi;Gail Reif;J. Calvet;D. Wallace
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作者：
Tamio Yamaguchi;Gail Reif;J. Calvet;D. Wallace
在常染色体显性遗传性多囊肾病（ADPKD）中，肾上皮细胞的异常增殖是形成充满囊液的囊肿、肾脏大面积肿大和肾功能进行性丧失的原因。cAMP激动剂，包括精氨酸加压素，通过蛋白激酶A激活B-Raf/MEK/细胞外信号调节激酶（ERK）信号传导途径加速囊肿上皮细胞增殖。cAMP的促有丝分裂作用与生长因子刺激作用同样有效和相加。在这里，我们确定了索拉非尼（BAY 43-9006），一种小分子Raf抑制剂，是否抑制来自人ADPKD肾囊肿的细胞增殖。我们发现，纳摩尔浓度的索拉非尼降低了ERK的基础活性，抑制了cAMP依赖性的B-Raf和MEK/ERK信号转导的激活，并引起了cAMP、表皮生长因子或两种激动剂组合诱导的细胞增殖的浓度依赖性抑制。索拉非尼完全阻断在三维胶原凝胶内培养的人ADPKD囊性细胞的体外囊肿生长。这些数据表明，人ADPKD囊肿上皮细胞的cAMP依赖性增殖被索拉非尼阻断，并表明小分子B-Raf抑制剂可能是降低cAMP对囊肿扩张的促有丝分裂作用的治疗选择。
In autosomal dominant polycystic kidney disease (ADPKD), aberrant proliferation of the renal epithelial cells is responsible for the formation of numerable fluid-filled cysts, massively enlarged kidneys, and progressive loss of renal function. cAMP agonists, including arginine vasopressin, accelerate cyst epithelial cell proliferation through protein kinase A activation of the B-Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway. The mitogenic effect of cAMP is equally potent and additive to growth factor stimulation. Here, we determined whether Sorafenib (BAY 43-9006), a small molecule Raf inhibitor, inhibits proliferation of cells derived from the cysts of human ADPKD kidneys. We found that nanomolar concentrations of Sorafenib reduced the basal activity of ERK, inhibited cAMP-dependent activation of B-Raf and MEK/ERK signaling, and caused a concentration-dependent inhibition of cell proliferation induced by cAMP, epidermal growth factor, or the combination of the two agonists. Sorafenib completely blocked in vitro cyst growth of human ADPKD cystic cells cultured within a three-dimensional collagen gel. These data demonstrate that cAMP-dependent proliferation of human ADPKD cyst epithelial cells is blocked by Sorafenib and suggest that small molecule B-Raf inhibitors may be a therapeutic option to reduce the mitogenic effects of cAMP on cyst expansion.