Evangelopoulos Maria Elephteria, Weis Joachim, Krüttgen Alex
Division of Neuropathology, Institute of Pathology, University of Bern, Murtenstr. 31, CH-3010 Bern, Switzerland.
Oncogene. 2005 May 5;24(20):3309-18. doi: 10.1038/sj.onc.1208494.
Neuroblastoma is the second most common pediatric malignancy, characterized by a high rate of unexplained spontaneous remissions. Much progress has been made in understanding neuroblastoma differentiation triggered by certain agents such as retinoic acid. However, little is known about the signalling pathways that lead to differentiation of neuroblastoma cells due to serum withdrawal. We found that in Neuro2a neuroblastoma cells, EGFR, ERK1/2 and Akt showed increased phosphorylation after serum withdrawal, and that the activation of EGFR was necessary for the activation of Akt and ERK1/2. Inhibition of EGFR, ERK1/2 and PI3K blocked neuroblastoma differentiation after serum withdrawal. Interestingly, addition of high-density lipoprotein (HDL) abrogated serum-withdrawal induced neuroblastoma differentiation, as well as the activation of EGFR. Our results demonstrate a novel role for serum-derived lipoproteins in the control of receptor tyrosine kinase activity.
神经母细胞瘤是第二常见的儿童恶性肿瘤，其特征是不明原因的自发缓解率很高。在理解由某些因子（如视黄酸）触发的神经母细胞瘤分化方面已经取得了很大进展。然而，对于血清剥夺导致神经母细胞瘤细胞分化的信号通路知之甚少。我们发现，在Neuro2a神经母细胞瘤细胞中，血清剥夺后表皮生长因子受体（EGFR）、细胞外信号调节激酶1/2（ERK1/2）和蛋白激酶B（Akt）的磷酸化增加，并且EGFR的激活对于Akt和ERK1/2的激活是必需的。抑制EGFR、ERK1/2和磷脂酰肌醇-3-激酶（PI3K）可阻断血清剥夺后的神经母细胞瘤分化。有趣的是，添加高密度脂蛋白（HDL）可消除血清剥夺诱导的神经母细胞瘤分化以及EGFR的激活。我们的结果证明了血清来源的脂蛋白在控制受体酪氨酸激酶活性方面的新作用。
