Ableson kinases negatively regulate invadopodia function and invasion in head and neck squamous cell carcinoma by inhibiting an HB-EGF autocrine loop.
Ableson kinases negatively regulate invadopodia function and invasion in head and neck squamous cell carcinoma by inhibiting an HB-EGF autocrine loop.
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DOI：
10.1038/onc.2012.513
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发表时间：
2013-10
期刊：
影响因子：
8
通讯作者：
Weed, S. A.
中科院分区：
文献类型：
--
作者：
Hayes, K. E.;Walk, E. L.;Ammer, A. G.;Kelley, L. C.;Martin, K. H.;Weed, S. A.
头颈部鳞状细胞癌(HNSCC)具有局部侵袭的倾向。HNSCC部分通过对细胞外基质(ECM)的蛋白分解来调节侵袭。表皮生长因子受体(EGFR)下游的Src、ERK1/2、Abl和Arg的激活通过使肌动蛋白调节蛋白Cortactin的磷酸化来调节不定形的活性。在MDA-MB-231乳腺癌细胞中，Abl和Arg作用于Src下游，使Cortactin磷酸化，促进内向ECM降解活性，从而为Ableson激酶分配亲侵袭作用。我们报告了Abl激酶在HNSCC中具有相反的负向调节作用，在HNSCC中它们抑制内翻和肿瘤侵袭。甲磺酸伊马替尼抑制Abl表达或Abl激酶活性促进HNSCC基质降解和3D胶原侵袭，这些功能在MDA-MB-231中受到损害。EGFR和Src活性升高的HNSCC细胞不存在Abl和Arg激酶活性升高，提示Src可以绕过Abl/Arg磷酸化皮质肌动蛋白，促进内毒素的降解。Src转化的Abl−/−/Arg−/−成纤维细胞产生细胞外基质降解含有pY42 1 Cortactin的失足动物，表明Abl/Arg在该系统中对失足动物的功能是必不可少的。伊马替尼作用于HNSCC细胞后，EGFR、ERK1/2和Src活性增强，失眠功能所需的Cortactin pY421和pS405/418增强。伊马替尼刺激HNSCC细胞脱落EGFR配体肝素结合的EGF样生长因子(HB-EGF)，其中可溶性HB-EGF促进HNSCC对失调型ECM的降解，但对MDA-MB-231无影响。用EGFR失活途径的抑制剂处理HNSCC细胞表明，EGFR和Src是失活功能所必需的。综上所述，我们的结果表明，Abl激酶通过抑制HB-EGF自分泌环路来负向调节HNSCC的侵袭过程，该环负责激活EGFR-Src-Cortactin级联反应，而Abl激酶在乳腺癌和其他类型的癌症中具有促进侵袭的功能。我们的结果为使用伊马替尼最近失败的HNSCC临床试验提供了机制支持。
Head and neck squamous cell carcinoma (HNSCC) has a proclivity for locoregional invasion. HNSCC mediates invasion in part through invadopodia-based proteolysis of the extracellular matrix (ECM). Activation of Src, Erk1/2, Abl and Arg downstream of epidermal growth factor receptor (EGFR) modulates invadopodia activity through phosphorylation of the actin regulatory protein cortactin. In MDA-MB-231 breast cancer cells, Abl and Arg function downstream of Src to phosphorylate cortactin, promoting invadopodia ECM degradation activity and thus assigning a pro-invasive role for Ableson kinases. We report that Abl kinases have an opposite, negative regulatory role in HNSCC where they suppress invadopodia and tumor invasion. Impairment of Abl expression or Abl kinase activity with imatinib mesylate enhanced HNSCC matrix degradation and 3D collagen invasion, functions that were impaired in MDA-MB-231. HNSCC lines with elevated EGFR and Src activation did not contain increased Abl or Arg kinase activity, suggesting Src could bypass Abl/Arg to phosphorylate cortactin and promote invadopodia ECM degradation. Src transformed Abl−/−/Arg−/− fibroblasts produced ECM degrading invadopodia containing pY421 cortactin, indicating that Abl/Arg are dispensable for invadopodia function in this system. Imatinib treated HNSCC cells had increased EGFR, Erk1/2 and Src activation, enhancing cortactin pY421 and pS405/418 required for invadopodia function. Imatinib stimulated shedding of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) from HNSCC cells, where soluble HB-EGF enhanced invadopodia ECM degradation in HNSCC but not in MDA-MB-231. HNSCC cells treated with inhibitors of the EGFR invadopodia pathway indicated that EGFR and Src are required for invadopodia function. Collectively our results indicate that Abl kinases negatively regulate HNSCC invasive processes through suppression of an HB-EGF autocrine loop responsible for activating a EGFR-Src-cortactin cascade, in contrast to the invasion promoting functions of Abl kinases in breast and other cancer types. Our results provide mechanistic support for recent failed HNSCC clinical trials utilizing imatinib.
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影响因子：
6.2
作者：
Araujo JC;Mathew P;Armstrong AJ;Braud EL;Posadas E;Lonberg M;Gallick GE;Trudel GC;Paliwal P;Agrawal S;Logothetis CJ
通讯作者：
Logothetis CJ
影响因子：
3.1
作者：
Gucalp A;Sparano JA;Caravelli J;Santamauro J;Patil S;Abbruzzi A;Pellegrino C;Bromberg J;Dang C;Theodoulou M;Massague J;Norton L;Hudis C;Traina TA
通讯作者：
Traina TA
影响因子：
3.7
作者：
Hatakeyama H;Cheng H;Wirth P;Counsell A;Marcrom SR;Wood CB;Pohlmann PR;Gilbert J;Murphy B;Yarbrough WG;Wheeler DL;Harari PM;Guo Y;Shyr Y;Slebos RJ;Chung CH
通讯作者：
Chung CH
影响因子：
7.3
作者：
Colicelli J
通讯作者：
Colicelli J
影响因子：
4
作者：
Antoku, Susumu;Saksela, Kalle;Mayer, Bruce J.
通讯作者：
Mayer, Bruce J.