Acquired Activation of the Akt/Cyclooxygenase-2/Mcl-1 Pathway Renders Lung Cancer Cells Resistant to Apoptosis
Acquired Activation of the Akt/Cyclooxygenase-2/Mcl-1 Pathway Renders Lung Cancer Cells Resistant to Apoptosis
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DOI：
10.1124/mol.109.061226
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发表时间：
2010-03-01
影响因子：
3.6
通讯作者：
Lin, Yong
中科院分区：
文献类型：
--
作者：
Chen, Wenjie;Bai, Lang;Lin, Yong
获得性细胞凋亡抵抗在肿瘤细胞化疗过程中的获得性耐药中起重要作用。我们以前的观察表明，肺癌细胞获得性肿瘤坏死因子相关的凋亡诱导配体抵抗与Akt介导的细胞FLICE样抑制蛋白(c-Flip)和Mcl-1的稳定有关。在这篇报道中，我们确定这些细胞也获得了对化疗药物如顺铂和阿霉素(阿霉素)诱导的凋亡的抵抗力，这是在体外细胞培养和体内移植瘤中检测到的。我们进一步发现，环氧合酶-2(COX-2)在获得性凋亡抵抗的细胞中显著过表达。COX-2似乎是获得性细胞凋亡抵抗的重要介质，因为用化学抑制剂抑制COX-2活性或用COX-2小干扰RNA降低COX-2蛋白表达水平可显著减轻对治疗诱导的细胞凋亡的抵抗。抑制Akt可显著抑制COX-2的表达，提示COX-2是该细胞存活激酶介导的细胞凋亡抵抗的下游效应因子。此外，当COX-2被抑制时，Mcl-1的表达显著减少，但不是c-flip，并且Mcl-1的敲除显著增加了细胞对凋亡的敏感性。我们的结果建立了一条由Akt、COX-2和Mcl-1组成的获得性细胞凋亡抵抗的新途径，这可能是规避肺癌获得性化疗耐药的分子靶点。
Acquired apoptosis resistance plays an important role in acquired chemoresistance in cancer cells during chemotherapy. Our previous observations demonstrated that acquired tumor necrosis factor-related apoptosis-inducing ligand resistance in lung cancer cells was associated with Akt-mediated stabilization of cellular FLICE-like inhibitory protein (c-FLIP) and Mcl-1. In this report, we determined that these cells also have acquired resistance to apoptosis induced by chemotherapeutics such as cisplatin and doxorubicin (Adriamycin), which was detected in vitro in cell cultures and in vivo in xenografted tumors. We further found that cyclooxygenase-2 (COX-2) is dramatically overexpressed in cells with acquired apoptosis resistance. COX-2 seems to be a crucial mediator in acquired apoptosis resistance because suppressing COX-2 activity with a chemical inhibitor or reducing COX-2 protein expression level with COX-2 small interfering RNA dramatically alleviated resistance to therapeutic-induced apoptosis. Inhibiting Akt markedly suppressed COX-2 expression, suggesting COX-2 is a downstream effector of this cell survival kinase-mediated apoptosis resistance. Furthermore, the expression of Mcl-1 but not c-FLIP was significantly reduced when COX-2 was suppressed, and knockdown of Mcl-1 substantially sensitized the cells to apoptosis. Our results establish a novel pathway that consists of Akt, COX-2, and Mcl-1 for acquired apoptosis resistance, which could be a molecular target for circumventing acquired chemoresistance in lung cancer.