Lay Jong-Ding, Hong Chih-Chen, Huang Jhy-Shrian, Yang Ya-Yu, Pao Chung-Yi, Liu Ching-Hang, Lai Yi-Pin, Lai Gi-Ming, Cheng Ann-Lii, Su Ih-Jen, Chuang Shuang-En
Institute of Cancer Research and Division of Clinical Research, National Health Research Institutes, No. 161 Min-Chuan East Road Section 6, Taipei 114, Taiwan.
Cancer Res. 2007 Apr 15;67(8):3878-87. doi: 10.1158/0008-5472.CAN-06-3191.
Metastasis and drug resistance are the major causes of mortality in patients with non-small cell lung cancer (NSCLC). Several receptor tyrosine kinases (RTKs), including AXL, are involved in the progression of NSCLC. The AXL/MER/SKY subfamily is involved in cell adhesion, motility, angiogenesis, and signal transduction and may play a significant role in the invasiveness of cancer cells. Notably, no specific inhibitors of AXL have been described. A series of CL1 sublines with progressive invasiveness established from a patient with NSCLC has been identified that positively correlates with AXL expression and resistance to chemotherapeutic drugs. The ectopic overexpression of AXL results in elevated cell invasiveness and drug resistance. Nuclear factor-kappaB (NF-kappaB) signaling activity is associated with AXL expression and may play an important role in the enhancement of invasiveness and doxorubicin resistance, as shown by using the NF-kappaB inhibitor, sulfasalazine, and IkappaB dominant-negative transfectants. In the current study, sulfasalazine exerted a synergistic anticancer effect with doxorubicin and suppressed cancer cell invasiveness in parallel in CL1 sublines and various AXL-expressing cancer cell lines. Phosphorylation of AXL and other RTKs (ErbB2 and epidermal growth factor receptor) was abolished by sulfasalazine within 15 min, suggesting that the inhibition of NF-kappaB and the kinase activity of RTKs are involved in the pharmacologic effects of sulfasalazine. Our study suggests that AXL is involved in NSCLC metastasis and drug resistance and may therefore provide a molecular basis for RTK-targeted therapy using sulfasalazine to enhance the efficacy of chemotherapy in NSCLC.
转移和耐药是导致非小细胞肺癌（NSCLC）患者死亡的主要原因。包括AXL在内的几种受体酪氨酸激酶（RTK）参与了NSCLC的进展。AXL/MER/SKY亚家族参与细胞黏附、迁移、血管生成和信号转导，可能在癌细胞的侵袭性中发挥重要作用。值得注意的是，尚未有AXL特异性抑制剂的报道。已从一名NSCLC患者中鉴定出一系列具有渐进侵袭性的CL1亚系，其与AXL表达及对化疗药物的耐药呈正相关。AXL的异位过表达导致细胞侵袭性和耐药性升高。核因子κB（NF-κB）信号活性与AXL表达相关，并且在增强侵袭性和多柔比星耐药性方面可能起重要作用，使用NF-κB抑制剂柳氮磺胺吡啶和IκB显性阴性转染体的实验证明了这一点。在本研究中，柳氮磺胺吡啶与多柔比星发挥协同抗癌作用，并在CL1亚系和各种表达AXL的癌细胞系中同时抑制癌细胞侵袭性。柳氮磺胺吡啶在15分钟内消除了AXL和其他RTK（ErbB2和表皮生长因子受体）的磷酸化，这表明抑制NF-κB和RTK的激酶活性参与了柳氮磺胺吡啶的药理作用。我们的研究表明AXL参与NSCLC转移和耐药，因此可能为使用柳氮磺胺吡啶进行RTK靶向治疗以提高NSCLC化疗疗效提供分子基础。
