Dreier Agnieszka, Barth Stefan, Goswami Anand, Weis Joachim
Medical Faculty, Institute of Neuropathology, RWTH Aachen University, Pauwelsstr 30, 52074 Aachen, Germany.
Tumour Biol. 2012 Feb;33(1):85-94. doi: 10.1007/s13277-011-0248-4. Epub 2011 Oct 11.
Dysregulation of growth factor receptors such as the epidermal growth factor receptor (EGFR) and of its truncated form EGFRvIII is frequently found in human tumors. EGFRvIII is a promising target for selective molecular tumor therapy because it is exclusively expressed by tumor cells. Cetuximab/Erbitux is a monoclonal antibody which targets EGFR and EGFRvIII. The effects of cetuximab on EGFRvIII but still the exact function and mechanism of cetuximab in relation to EGFR and EGFRvIII are incompletely understood. Therefore, we investigated the influence of cetuximab on EGFRvIII signaling and cellular survival. We found that cetuximab leads to increased internalization of EGFRvIII in NR6M cells but is unable to inhibit neither the activation of EGFRvIII nor its downstream signaling pathways. Incubation with cetuximab also did not alter the survival and proliferation of EGFRvIII-expressing cells. However, it caused increased mitochondrial activity and an increase in co-localization of EGFRvIII with mitochondria. These results demonstrate that interaction of EGFRvIII with mitochondria could play a role in survival of cetuximab-treated NR6M cells. Thus, a role of mitochondria in resistance to cetuximab has to be considered.
诸如表皮生长因子受体（EGFR）及其截短形式EGFRvIII等生长因子受体的失调在人类肿瘤中经常被发现。EGFRvIII是选择性分子肿瘤治疗的一个有前景的靶点，因为它仅在肿瘤细胞中表达。西妥昔单抗/爱必妥是一种靶向EGFR和EGFRvIII的单克隆抗体。西妥昔单抗对EGFRvIII的作用，但西妥昔单抗与EGFR和EGFRvIII相关的确切功能和机制仍未完全了解。因此，我们研究了西妥昔单抗对EGFRvIII信号传导和细胞存活的影响。我们发现西妥昔单抗导致NR6M细胞中EGFRvIII的内化增加，但既不能抑制EGFRvIII的激活，也不能抑制其下游信号通路。用西妥昔单抗孵育也没有改变表达EGFRvIII的细胞的存活和增殖。然而，它导致线粒体活性增加以及EGFRvIII与线粒体的共定位增加。这些结果表明，EGFRvIII与线粒体的相互作用可能在西妥昔单抗处理的NR6M细胞的存活中起作用。因此，必须考虑线粒体在对西妥昔单抗耐药中的作用。
