Loss of tyrosine phosphatase-dependent inhibition promotes activation of tyrosine kinase c-Src in detached pancreatic cells.
Loss of tyrosine phosphatase-dependent inhibition promotes activation of tyrosine kinase c-Src in detached pancreatic cells.
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DOI：
10.1002/mc.20684
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发表时间：
2010-12
影响因子：
4.6
通讯作者：
Summy, Justin M.
中科院分区：
文献类型：
--
作者：
Connelly, Sarah F.;Isley, Beth A.;Baker, Cheryl H.;Gallick, Gary E.;Summy, Justin M.
尽管人们高度关注新型治疗策略，但胰腺癌仍然是最致命的人类恶性肿瘤之一。与胰腺癌相关的频繁和快速死亡率可能归因于几个因素，包括晚期诊断、肿瘤快速侵入周围组织和远处转移的形成。局部侵袭和转移都需要破坏肿瘤细胞与细胞外基质的接触。正常细胞与细胞外基质的分离导致一种称为失巢凋亡的程序性细胞死亡。胰腺癌细胞通过激活允许非粘附依赖性存活的信号通路来避免失巢凋亡。在本研究中，检测了在分离的胰腺癌细胞中激活的细胞信号传导途径。我们证明了一个快速和强大的激活Src激酶在分离的胰腺癌细胞，相对于粘附。在存在或不存在特定细胞外基质蛋白的情况下，重新附着到组织培养塑料后，Src自磷酸化迅速恢复到基线水平。用酪氨酸磷酸酶抑制剂治疗胰腺癌细胞增加了贴壁细胞中稳态Src自磷酸化，并消除了抑制剂诱导的Src自磷酸化增加。在胰腺癌细胞中发现Src与含有Src同源2（SH 2）结构域的蛋白酪氨酸磷酸酶（SHP-2）共沉淀，表明SHP-2可能参与粘附细胞中Src自磷酸化的调节。在分离的细胞中观察到Akt和Jun N末端激酶（JNK）磷酸化的Src家族激酶（SFK）依赖性增加，这表明已从细胞外基质分离的胰腺癌细胞中生存和应激途径可能存在Src依赖性激活。
Despite an intense focus on novel therapeutic strategies, pancreatic adenocarcinoma remains one of the deadliest human malignancies. The frequent and rapid mortality associated with pancreatic cancer may be attributed to several factors, including late diagnosis, rapid tumor invasion into surrounding tissues, and formation of distant metastases. Both local invasion and metastasis require disruption of tumor cell contacts with the extracellular matrix. Detachment of normal cells from the extracellular matrix leads to a form of programmed cell death termed anoikis. Pancreatic cancer cells avert anoikis by activation of signaling pathways that allow for adhesion-independent survival. In the present studies, cellular signaling pathways activated in detached pancreatic cancer cells were examined. We demonstrate a rapid and robust activation of Src kinase in detached pancreatic cancer cells, relative to adherent. Src autophosphorylation rapidly returned to baseline levels upon reattachment to tissue culture plastic, in the presence or absence of specific extracellular matrix proteins. Treatment of pancreatic cancer cells with tyrosine phosphatase inhibitors increased steady-state Src autophosphorylation in adherent cells and abrogated the detachment-induced increase in Src autophosphorylation. Src was found to co-immunoprecipitate with the Src Homology 2 (SH2) domain containing protein tyrosine phosphatase (SHP-2) in pancreatic cancer cells, suggesting that SHP-2 may participate in regulation of Src autophosphorylation in adherent cells. Src family kinase (SFK) dependent increases in Akt and Jun N-terminal kinase (JNK) phosphorylation were observed in detached cells, indicating the potential for Src-dependent activation of survival and stress pathways in pancreatic cancer cells that have detached from the extracellular matrix.
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