Activation of focal adhesion kinase enhances the adhesion and invasion of pancreatic cancer cells via extracellular signal-regulated kinase-1/2 signaling pathway activation.
Activation of focal adhesion kinase enhances the adhesion and invasion of pancreatic cancer cells via extracellular signal-regulated kinase-1/2 signaling pathway activation.
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局灶性粘附激酶的激活通过细胞外信号调节的激酶-1/2信号传导途径激活来增强胰腺癌细胞的粘附和侵袭。
DOI：
10.1186/1476-4598-4-37
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发表时间：
2005-10-06
期刊：
影响因子：
37.3
通讯作者：
Manabe, Tadao
中科院分区：
文献类型：
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作者：
Sawai, Hirozumi;Okada, Yuji;Funahashi, Hitoshi;Matsuo, Yoichi;Takahashi, Hiroki;Takeyama, Hiromitsu;Manabe, Tadao
与整合素和粘着斑激酶（FAK）的相互作用调节癌细胞粘附和侵袭细胞外基质（ECM）。此外，FAK的磷酸化与细胞运动性和侵袭性的增加相关。癌细胞在多种ECM蛋白（包括IV型胶原（科尔IV））上的粘附和扩散导致FAK的酪氨酸磷酸化和活化的增加。本研究探讨了白细胞介素（IL）-1α激活FAK及其下游细胞外信号调节激酶（ERK）-1/2信号通路，促进胰腺癌细胞与ECM粘附，进而增强胰腺癌细胞粘附和侵袭的机制。免疫印迹分析显示，AsPC-1、BxPC-3和Capan-2三种胰腺癌细胞株均表达FAK和β1整合素蛋白。当细胞接种于科尔IV上时，用IL-1α刺激可进一步增强FAK蛋白与β1整合素的结合。抗β1整合素抗体预孵育及FAK siRNA转染可抑制胰腺癌细胞FAK与β1整合素的结合。粘附于科尔IV的胰腺癌细胞可观察到FAK磷酸化，IL-1α刺激粘附于科尔IV的胰腺癌细胞可观察到更强的FAK磷酸化，且呈时间依赖性。酪氨酸激酶抑制剂Genistein可明显抑制FAK的磷酸化。IL-1α刺激和科尔IV粘附增强Ras的活化，如胰腺癌细胞中Ras-GTP水平增加所证明的。Ras的激活与ERK的磷酸化相关。IL-1α诱导的胰腺癌细胞对科尔IV的粘附和侵袭在不影响胰腺癌细胞凋亡的情况下，通过siRNA沉默FAK基因、阻断β1整合素和抑制FAK磷酸化而被抑制。MEK抑制剂PD 98059也可抑制IL-1α诱导的胰腺癌细胞粘附和侵袭的增强。 我们的研究结果表明FAK的激活通过Ras/ERK信号通路参与胰腺癌的侵袭能力。基于我们的研究结果，我们认为IL-1，FAK和整合素功能的修饰可能是胰腺癌侵袭性扩散的一种新的治疗方法。
Interaction with integrin and focal adhesion kinase (FAK) regulates the cancer cell adhesion and invasion into extracellular matrix (ECM). In addition, phosphorylation of FAK correlates with the increase of cell motility and invasion. Adhesion and spreading of cancer cells on a variety of ECM proteins, including collagen type IV (Coll IV), leads to an increase in tyrosine phosphorylation and activation of FAK. In this study, we investigated the mechanism of activation of FAK and its downstream extracellular signal-regulated kinase (ERK)-1/2 signaling following stimulation by interleukin (IL)-1α and adhesion to ECM with subsequent enhancement of pancreatic cancer cell adhesion and invasion. In immunoblotting analysis, all three pancreatic cancer cell lines (AsPC-1, BxPC-3, and Capan-2) expressed the protein of FAK and β1 integrin. Enhancement of FAK protein association with β1 integrin when cells were plated on Coll IV was more increased by stimulation with IL-1α. Preincubation with anti-β1 integrin antibody and FAK siRNA transfection inhibited the association of FAK with β1 integrin of pancreatic cancer cells. FAK phosphorylation was observed by adhesion to Coll IV, furthermore, stronger FAK phosphorylation was observed by stimulation with IL-1α of pancreatic cancer cells adhered to Coll IV in time-dependent manner. Genistein, a tyrosine kinase inhibitor, markedly inhibited the FAK phosphorylation. IL-1α stimulation and Coll IV adhesion enhanced the activation of Ras, as evidenced by the increased Ras-GTP levels in pancreatic cancer cells. Activation of Ras correlated with the phosphorylation of ERK. While not statistical affecting the apoptosis of pancreatic cancer cells, IL-1α-induced adhesion and invasion on Coll IV were inhibited with FAK gene silencing by siRNA, β1 integrin blocking, and inhibition of FAK phosphorylation. PD98059, a MEK inhibitor, also inhibited IL-1α-induced enhancement of adhesion and invasion in pancreatic cancer cells. Our results demonstrated that activation of FAK is involved with the aggressive capability in pancreatic cancer through Ras/ERK signaling pathway. Based on our results, we suggest that the modification of IL-1, FAK, and integrins functions might be a novel therapeutic approach to aggressive spread of pancreatic cancer.
影响因子：
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作者：
Wu RC;Blumenthal M;Li X;Schönthal AH
通讯作者：
Schönthal AH