Tyrosine kinase-dependent, phosphatidylinositol 3'-kinase, and mitogen-activated protein kinase-independent signaling pathways prevent lung adenocarcinoma cells from anoikis.
Tyrosine kinase-dependent, phosphatidylinositol 3'-kinase, and mitogen-activated protein kinase-independent signaling pathways prevent lung adenocarcinoma cells from anoikis.
复制标题
DOI：
--
复制
发表时间：
2001-03
期刊：
影响因子：
11.2
通讯作者：
L. Wei;Y. Yang;Q. Yu
中科院分区：
文献类型：
--
作者：
L. Wei;Y. Yang;Q. Yu
正常的上皮细胞是锚定依赖性的。正常上皮细胞从其基底层脱落引起凋亡，称为失巢凋亡。然而，恶性肿瘤细胞可以独立于锚定而存活和增殖。为了了解肿瘤细胞锚定独立性的分子基础，我们研究了酪氨酸激酶及其下游信号通路在人肺腺癌细胞抗失巢凋亡中的作用。分析的五种肺腺癌细胞系中有四种对失巢凋亡具有抗性。酪氨酸激酶抑制剂genistein使其中三个敏感的失巢凋亡。虽然细胞脱离诱导快速蛋白酪氨酸脱磷酸化的Madin-Darby犬肾细胞，一个非转化的上皮细胞系，酪氨酸磷酸化的几种蛋白质在肿瘤细胞是锚定独立的。同样，Akt和丝裂原活化蛋白激酶（酪氨酸激酶下游的两种信号蛋白）的磷酸化在Madin-Darby犬肾细胞中减少，但在细胞脱离后的一些肿瘤细胞中增加。然而，抑制这两种蛋白的磷酸化并不诱导肿瘤细胞的失巢凋亡。几种已知的酪氨酸激酶的特异性抑制剂也未能诱导这些细胞的失巢凋亡。这些数据表明存在酪氨酸激酶依赖性磷脂酰肌醇3 '-激酶和丝裂原活化蛋白激酶非依赖性信号通路，其功能是调节细胞存活和死亡。这些通路的改变可能与肺腺癌细胞和其他恶性肿瘤细胞的锚定非依赖性存活有关。
Normal epithelial cells are anchorage-dependent. Detachment of normal epithelial cells from their substratum causes apoptosis, termed anoikis. Malignant tumor cells, however, can survive and proliferate independent of anchorage. To understand the molecular basis of tumor cell anchorage independence, we investigated the role of tyrosine kinases and their downstream signaling pathways in anoikis resistance of human lung adenocarcinoma cells. Four of the five lung adenocarcinoma cell lines analyzed are resistant to anoikis. Tyrosine kinase inhibitor genistein rendered three of them sensitive to anoikis. Although cell detachment induced rapid protein tyrosine dephosphorylation in Madin-Darby canine kidney cells, a nontransformed epithelial cell line, tyrosine phosphorylation of several proteins in the tumor cells is anchorage-independent. Similarly, phosphorylation of Akt and mitogen-activated protein kinase, two signaling proteins downstream of tyrosine kinases, was decreased in Madin-Darby canine kidney cells but increased in some of the tumor cells upon cell detachment. Inhibition of phosphorylation of the two proteins, however, did not induce anoikis in the tumor cells. Specific inhibitors to several known tyrosine kinases also failed to induce anoikis in these cells. These data suggest the existence of tyrosine kinase-dependent phosphatidylinositol 3'-kinase and mitogen-activated protein kinase-independent signaling pathways that function to regulate cell survival and death. Alteration in these pathways may count for the anchorage-independent survival of the lung adenocarcinoma cells and other malignant tumor cells.