Cáceres Mónica, Tobar Nicolás, Guerrero Javier, Smith Patricio C, Martínez Jorge
Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago, Chile.
J Cell Biochem. 2008 Feb 15;103(3):986-93. doi: 10.1002/jcb.21469.
In this study, we demonstrated that tyrosine phosphorylation of EGFR and the autocrine expression of uPA and HB-EGF depend on the activity of c-jun amino-terminal kinase (JNK) in human prostatic DU-145 cells. These cells overexpress EGFR and produce a high amount of uPA. Treatment with either SP600125, a specific chemical inhibitor of JNK, or the expression of a dominant-negative JNK form inhibited autocrine production of uPA and HB-EGF, which block EGFR phosphorylation and mitigates invasive capacity. Our data provided evidence that in DU-145 cells, the maintenance of the activation level of EGFR, which determines the cellular invasive potential, operates through an autocrine loop involving the JNK-dependent production of uPA and HB-EGF activity. Moreover, we found that exogenously added uPA stimulates autocrine production of HB-EGF, and that blocking HB-EGF activity curbed DU-145 cell invasive potential.
在本研究中，我们证明了在人前列腺DU - 145细胞中，表皮生长因子受体（EGFR）的酪氨酸磷酸化以及尿激酶型纤溶酶原激活物（uPA）和肝素结合表皮生长因子（HB - EGF）的自分泌表达依赖于c - jun氨基末端激酶（JNK）的活性。这些细胞过度表达EGFR并产生大量uPA。用SP600125（一种JNK的特异性化学抑制剂）处理，或表达显性负性JNK形式，均可抑制uPA和HB - EGF的自分泌产生，这会阻断EGFR磷酸化并减轻侵袭能力。我们的数据表明，在DU - 145细胞中，决定细胞侵袭潜能的EGFR激活水平的维持，是通过一个自分泌环起作用的，该自分泌环涉及JNK依赖的uPA产生和HB - EGF活性。此外，我们发现外源性添加的uPA刺激HB - EGF的自分泌产生，并且阻断HB - EGF活性可抑制DU - 145细胞的侵袭潜能。
