Sphingosine Kinase-1 Enhances Resistance to Apoptosis through Activation of PI3K/Akt/NF-κB Pathway in Human Non-Small Cell Lung Cancer
Sphingosine Kinase-1 Enhances Resistance to Apoptosis through Activation of PI3K/Akt/NF-κB Pathway in Human Non-Small Cell Lung Cancer
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DOI：
10.1158/1078-0432.ccr-10-0720
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发表时间：
2011-04-01
影响因子：
11.5
通讯作者：
Li, Mengfeng
中科院分区：
文献类型：
--
作者：
Song, Libing;Xiong, Huaping;Li, Mengfeng
目的：本研究旨在探讨鞘氨醇激酶-1（SPHK 1）对化疗药物诱导的非小细胞肺癌（NSCLC）细胞凋亡的影响及其在NSCLC进展中的临床意义。SPHK 1对化疗药物诱导的细胞凋亡的影响在体外和体内进行了检查，使用Annexin V染色和TUNEL（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）测定。结果：SPHK 1在NSCLC组织中的表达明显增加，且与NSCLC患者的肿瘤进展和不良生存率相关。SPHK 1的上调显著抑制阿霉素或紫杉醇诱导的细胞凋亡，与抗凋亡蛋白Bcl-xl，cIAP 1，c-IAP 2和TRAF 1的诱导相关。与此相反，沉默SPHK 1表达或用特异性抑制剂SK 1-I抑制SPHK 1活性显著增强NSCLC细胞对化疗药物诱导的凋亡的敏感性。此外，我们证明SPHK 1的上调激活了PI 3 K/Akt/NF-κ B通路，并且PI 3 K/Akt/NF-κ B通路的抑制消除了SPHK 1对NSCLC细胞的抗凋亡作用。我们的研究结果表明SPHK 1是治疗NSCLC的潜在药理学靶点，抑制SPHK 1表达或其激酶活性可能代表了一种新的策略，使NSCLC对化疗临床癌症研究; 17（7）; 1839-49。(C)2011年AACR。
Purpose: The present study was to examine the effect of sphingosine kinase-1 (SPHK1) on chemother-apeutics-induced apoptosis in non-small cell lung cancer (NSCLC) cells, which is relatively insensitive to chemotherapy, and its clinical significance in NSCLC progression.Experimental Design: The correlation of SPHK1 expression and clinical features of NSCLC was analyzed in 218 paraffin-embedded archived NSCLC specimens by immunohistochemical analysis. The effect of SPHK1 on apoptosis induced by chemotherapeutics was examined both in vitro and in vivo, using Annexin V staining and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assays. Western blotting and luciferase analysis were performed to examine the impact of SPHK1 on the PI3K/Akt /NF-kappa B signaling.Results: The expression of SPHK1 was markedly increased in NSCLC and correlated with tumor progression and poor survival of patients with NSCLC. Upregulation of SPHK1 significantly inhibited doxorubicin-or docetaxel-induced apoptosis, associated with induction of antiapoptotic proteins Bcl-xl, cIAP1, c-IAP2, and TRAF1. In contrast, silencing SPHK1 expression or inhibiting SPHK1 activity with specific inhibitor, SK1-I, significantly enhanced the sensitivity of NSCLC cells to apoptosis induced by chemotherapeutics both in vitro and in vivo. Moreover, we demonstrated that upregulation of SPHK1 activated the PI3K/Akt/NF-kappa B pathway, and that inhibition of the PI3K/Akt/NF-kappa B pathway abrogated the antiapoptotic effect of SPHK1 on NSCLC cells.Conclusions: Our results suggest that SPHK1 is a potential pharmacologic target for the treatment of NSCLC and inhibition of SPHK1 expression or its kinase activity might represent a novel strategy to sensitize NSCLC to chemotherapy. Clin Cancer Res; 17(7); 1839-49. (C) 2011 AACR.