Chronic exposure to cigarette smoke leads to activation of p21 (RAC1)-activated kinase 6 (PAK6) in non-small cell lung cancer cells.
Chronic exposure to cigarette smoke leads to activation of p21 (RAC1)-activated kinase 6 (PAK6) in non-small cell lung cancer cells.
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DOI：
10.18632/oncotarget.11310
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发表时间：
2016-09-20
期刊：
影响因子：
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通讯作者：
Chatterjee A
中科院分区：
文献类型：
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作者：
Raja R;Sahasrabuddhe NA;Radhakrishnan A;Syed N;Solanki HS;Puttamallesh VN;Balaji SA;Nanjappa V;Datta KK;Babu N;Renuse S;Patil AH;Izumchenko E;Prasad TS;Chang X;Rangarajan A;Sidransky D;Pandey A;Gowda H;Chatterjee A
流行病学数据明确表明吸烟是全世界肺癌的主要原因之一。近年来，靶向治疗已成为癌症治疗的首选方式之一。尽管某些靶向疗法（例如抗 EGFR）已投入临床实践，但它们在吸烟肺癌患者中所取得的成功有限。这需要通过系统研究香烟烟雾诱导的信号机制来发现替代药物靶点。为了研究响应香烟烟雾而激活的信号事件，我们对长期暴露于香烟烟雾的 H358 肺癌细胞进行了基于 SILAC 的磷酸蛋白质组学分析。我们鉴定了 1,812 个磷酸位点，其中 278 个磷酸位点在长期暴露于香烟烟雾的 H358 细胞中过度磷酸化（≥ 3 倍）。我们的数据揭示了 PAK6 保守激酶结构域内 S560 的过度磷酸化。 PAK6 的激活与癌症的各种过程（包括转移）相关。机制研究表明，抑制 PAK6 会导致经香烟烟雾处理的细胞的细胞增殖、迁移和侵袭减少。此外，siRNA 介导的 PAK6 沉默导致一组非小细胞肺癌 (NSCLC) 细胞的侵袭能力下降。一致地，携带肿瘤异种移植物的小鼠在用 PF-3758309（II 组 PAK 抑制剂）治疗后显示出肿瘤生长减少。免疫组织化学分析显示，组织微阵列中 66.6% (52/78) 的 NSCLC 病例中 PAK6 过度表达。总而言之，我们的研究表明 PAK6 是 NSCLC（尤其是吸烟者）有希望的新型治疗靶点。
Epidemiological data clearly establishes cigarette smoking as one of the major cause for lung cancer worldwide. Recently, targeted therapy has become one of the most preferred modes of treatment for cancer. Though certain targeted therapies such as anti-EGFR are in clinical practice, they have shown limited success in lung cancer patients who are smokers. This demands discovery of alternative drug targets through systematic investigation of cigarette smoke-induced signaling mechanisms. To study the signaling events activated in response to cigarette smoke, we carried out SILAC-based phosphoproteomic analysis of H358 lung cancer cells chronically exposed to cigarette smoke. We identified 1,812 phosphosites, of which 278 phosphosites were hyperphosphorylated (≥ 3-fold) in H358 cells chronically exposed to cigarette smoke. Our data revealed hyperphosphorylation of S560 within the conserved kinase domain of PAK6. Activation of PAK6 is associated with various processes in cancer including metastasis. Mechanistic studies revealed that inhibition of PAK6 led to reduction in cell proliferation, migration and invasion of the cigarette smoke treated cells. Further, siRNA mediated silencing of PAK6 resulted in decreased invasive abilities in a panel of non-small cell lung cancer (NSCLC) cells. Consistently, mice bearing tumor xenograft showed reduced tumor growth upon treatment with PF-3758309 (group II PAK inhibitor). Immunohistochemical analysis revealed overexpression of PAK6 in 66.6% (52/78) of NSCLC cases in tissue microarrays. Taken together, our study indicates that PAK6 is a promising novel therapeutic target for NSCLC, especially in smokers.