Plumbagin reduces osteopontin-induced invasion through inhibiting the Rho-associated kinase signaling pathway in A549 cells and suppresses osteopontin-induced lung metastasis in BalB/c mice
Plumbagin reduces osteopontin-induced invasion through inhibiting the Rho-associated kinase signaling pathway in A549 cells and suppresses osteopontin-induced lung metastasis in BalB/c mice
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DOI：
10.1016/j.bmcl.2017.03.047
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发表时间：
2017-05-01
影响因子：
2.7
通讯作者：
Lee, Eun-Ok
中科院分区：
文献类型：
--
作者：
Kang, Chi Gu;Im, Eunji;Lee, Eun-Ok
肺癌是美国男性和女性中第二大最常见的诊断癌症，也是癌症死亡的主要原因。骨桥蛋白（osteopontin，OPN）通过抑制黏着斑激酶（focal adhesion kinase，FAK）/AKT/Rho相关激酶（Rho-associated kinase，ROCK）信号通路诱导人非小细胞肺癌（non-small cell lung cancer，NSCLC）细胞的侵袭。白花丹素是从药用植物白花丹的根中分离出来的，据报道具有抗癌活性。然而，白花丹素抑制癌细胞侵袭的分子机制仍不清楚。在本研究中，白花丹素在OPN处理的NSCLC A549细胞中的抗侵袭和抗转移机制被研究。OPN可有效诱导NSCLC A549细胞和H1299细胞的运动和侵袭，但被白花丹素强烈抑制，无细胞毒性。此外，在白花丹素处理的细胞中，OPN在细胞前缘的片状伪足形成显著减少。白花丹素可有效抑制OPN诱导的ROCK 1表达以及LIM激酶1和2（LIMK 1/2）和cofilin的磷酸化。PPN诱导的FAIL和AKT的磷酸化被削弱，而不影响其总形式的白花丹碱处理。OPN促进转移性肺定植，这在白花丹素处理的小鼠中被有效抑制。综上所述，这些结果表明，白花丹素减少OPN诱导的NSCLC A549细胞的侵袭，这是由于抑制FAK/AKT通路介导的ROCK通路，并抑制体内肺转移。(C)2017爱思唯尔有限公司版权所有
Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths in both men and women in the United States. It has been recently demonstrated that osteopontin (OPN) effectively inhibits cofilin activity through the focal adhesion kinase (FAK)/AKT/Rho-associated kinase (ROCK) pathway to induce the invasion of human non-small cell lung cancer (NSCLC) cells. Plumbagin was isolated from the roots of the medicinal plant Plumbago zeylanica L and has been reported to possess anticancer activities. However, the molecular mechanisms by which plumbagin inhibits the invasion of cancer cells is still unclear. In this study, the anti-invasive and anti-metastatic mechanisms of plumbagin were investigated in OPN-treated NSCLC A549 cells. OPN effectively induced the motility and invasion of NSCLC A549 cells and H1299 cells, which was strongly suppressed by plumbagin with no evidence of cytotoxicity. In addition, lamellipodia formation at the leading edge of cells by OPN was dramatically decreased in plumbagin-treated cells. Plumbagin caused an effective inhibition in OPN-induced the expression of ROCK1 as well as the phosphorylation of LIM kinase 1 and 2 (LIMK1/2), and cofilin. OPN-induced the phosphorylation of FAIL and AKT was impaired without affecting their total forms by plumbagin treatment. OPN facilitated metastatic lung colonization, which was effectively suppressed in plumbagin-treated mice. Taken together, these results suggest that plumbagin reduces OPN-induced the invasion of NSCLC A549 cells, which resulted from inhibiting the ROCK pathway mediated by the FAK/AKT pathway and suppresses lung metastasis in vivo. (C) 2017 Elsevier Ltd. All rights reserved.