Versteeg Henri H, Spek C Arnold, Richel Dick J, Peppelenbosch Maikel P
Laboratory for Experimental Internal Medicine, G2-105, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Oncogene. 2004 Jan 15;23(2):410-7. doi: 10.1038/sj.onc.1207066.
The molecular mechanisms enabling cancer cells to survive loss-of-adhesion-induced apoptosis in the early phases of metastasis remain largely obscure. Interestingly, the overexpression of tissue factor (TF) on tumor cells is associated with successful metastasis and it has now become clear that coagulation factor VIIa (FVIIa), the natural binding partner of TF induces signal transduction in TF-expressing cells. Hence, we investigated the effects of FVIIa-TF interaction on cell survival. We observed that FVIIa, at physiologically relevant concentrations, inhibits cell death and caspase-3 activation induced by serum deprivation and loss of adhesion (lack of integrin signaling) in TF-overexpressing cells, but not in non-TF-expressing cells. This FVIIa effect was not dependent on the formation of the downstream coagulation products FXa or thrombin and was inhibited using an active site-blocked form of FVIIa (FVIIai). FVIIa incubation resulted in the prolonged activation of both the phosphatidylinositide-3-(OH) kinase and p42/p44 MAP kinase pathways, and studies employing pharmacological inhibitors revealed that both the pathways are required for FVIIa-induced cell survival and inhibition of caspase-3 activity. Finally, TF:FVIIa-induced FXa generation dramatically increased cell survival. We propose that FVIIa-induced cell survival may explain why overexpression of TF is associated with successful metastasis.
在转移早期，癌细胞如何在失去黏附诱导的凋亡中存活的分子机制仍不清楚。有趣的是，肿瘤细胞上组织因子（TF）的过表达与成功转移有关，现在已经明确，TF的天然结合伴侣凝血因子VIIa（FVIIa）可在表达TF的细胞中诱导信号转导。因此，我们研究了FVIIa-TF相互作用对细胞存活的影响。我们观察到，在生理相关浓度下，FVIIa可抑制TF过表达细胞中因血清剥夺和失去黏附（缺乏整合素信号）诱导的细胞死亡和半胱天冬酶-3激活，但对非TF表达细胞无此作用。FVIIa的这种作用不依赖于下游凝血产物FXa或凝血酶的形成，且可被活性位点封闭形式的FVIIa（FVIIai）抑制。FVIIa孵育导致磷脂酰肌醇-3-（OH）激酶和p42/p44丝裂原活化蛋白激酶途径的持续激活，使用药理抑制剂的研究表明，这两条途径都是FVIIa诱导细胞存活和抑制半胱天冬酶-3活性所必需的。最后，TF:FVIIa诱导的FXa生成显著提高了细胞存活率。我们认为，FVIIa诱导的细胞存活可能解释了为什么TF过表达与成功转移相关。
