Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response.
Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response.
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DOI：
10.1158/1541-7786.mcr-13-0458
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Tran NL
中科院分区：
文献类型：
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作者：
Whitsett TG;Mathews IT;Cardone MH;Lena RJ;Pierceall WE;Bittner M;Sima C;LoBello J;Weiss GJ;Tran NL
对标准临床干预（包括化疗、放疗和酪氨酸激酶抑制剂（TKI）治疗）的不敏感性仍然是改善非小细胞肺癌（NSCLC）患者预后的重大障碍。对耐药的分子机制仍知之甚少。已知TNF样弱凋亡诱导剂（TWEAK）-FGF诱导14（Fn 14）信号传导轴通过NF-κB活化和促存活Bcl-2家族成员的上调来促进癌细胞存活。在此，确定了TWEAK-Fn 14促存活信号传导通过髓细胞白血病序列1（Mcl-1）的上调在NSCLC中的作用。Mcl-1表达与人类原发性非小细胞肺癌肿瘤中的Fn 14表达、晚期非小细胞肺癌肿瘤分期和患者预后不良显着相关。TWEAK刺激NSCLC细胞诱导NF-κ B依赖性Mcl-1蛋白表达，并赋予Mcl-1依赖性化疗和放射抗性。使用EU-5148通过siRNA或药理学抑制Mcl-1消耗Mcl-1，使TWEAK处理的NSCLC细胞对顺铂或放射介导的细胞存活抑制敏感。此外，EU-5148在一组NSCLC细胞系中抑制细胞存活。相反，抑制Bcl-2/Bcl-xL功能对抑制TWEAK诱导的细胞存活的影响最小。总的来说，这些结果将TWEAK-Fn 14通过Mcl-1的信号传导定位为NSCLC肿瘤细胞存活的重要机制，并开辟了新的治疗途径来消除NSCLC中的高死亡率。TWEAK-Fn 14信号轴通过Mcl-1增强肺癌细胞存活和治疗抗性，将TWEAK-Fn 14和Mcl-1定位为肺癌的治疗机会。
Insensitivity to standard clinical interventions, including chemotherapy, radiotherapy and tyrosine kinase inhibitor (TKI) treatment, remains a substantial hindrance towards improving the prognosis of patients with non-small cell lung cancer (NSCLC). The molecular mechanism of therapeutic resistance remains poorly understood. The TNF-like weak inducer of apoptosis (TWEAK)-FGF-inducible 14 (Fn14) signaling axis is known to promote cancer cell survival via NF-κB activation and the up-regulation of pro-survival Bcl-2 family members. Here, a role was determined for TWEAK-Fn14 pro-survival signaling in NSCLC through the up-regulation of myeloid cell leukemia sequence 1 (Mcl-1). Mcl-1 expression significantly correlated with Fn14 expression, advanced NSCLC tumor stage, and poor patient prognosis in human primary NSCLC tumors. TWEAK stimulation of NSCLC cells induced NF-κB-dependent Mcl-1 protein expression and conferred Mcl-1-dependent chemo- and radio-resistance. Depletion of Mcl-1 via siRNA or pharmacological inhibition of Mcl-1, using EU-5148, sensitized TWEAK-treated NSCLC cells to cisplatin- or radiation-mediated inhibition of cell survival. Moreover, EU-5148 inhibited cell survival across a panel of NSCLC cell lines. In contrast, inhibition of Bcl-2/Bcl-xL function had minimal effect on suppressing TWEAK-induced cell survival. Collectively, these results position TWEAK-Fn14 signaling through Mcl-1 as a significant mechanism for NSCLC tumor cell survival, and open new therapeutic avenues to abrogate the high mortality rate seen in NSCLC. The TWEAK-Fn14 signaling axis enhances lung cancer cell survival and therapeutic resistance through Mcl-1, positioning both TWEAK-Fn14 and Mcl-1 as therapeutic opportunities in lung cancer.