Enhanced tumor suppression by an ING4/IL-24 bicistronic adenovirus-mediated gene cotransfer in human non-small cell lung cancer cells
Enhanced tumor suppression by an ING4/IL-24 bicistronic adenovirus-mediated gene cotransfer in human non-small cell lung cancer cells
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DOI：
10.1038/cgt.2011.31
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发表时间：
2011-06
影响因子：
6.4
通讯作者：
Y. Zhu;H. Lv;Y. Xie;W. Sheng;J. Xiang;J. Yang
中科院分区：
文献类型：
--
作者：
Y. Zhu;H. Lv;Y. Xie;W. Sheng;J. Xiang;J. Yang
ING 4作为生长抑制因子（inhibitor of growth，ING）家族中的一员，对多种肿瘤具有较强的抑制作用。白细胞介素-24（IL-24）是一种肿瘤抑制因子，具有广谱和肿瘤特异性的抗肿瘤活性。本研究构建了ING 4/IL-24双顺反子腺病毒（Ad-ING 4-IL-24），并研究了其对人非小细胞肺癌A549细胞的体外和体内联合作用。我们证明，通过腺病毒介导的ING 4和IL-24共表达的ING 4和IL-24联合处理诱导了体外A549肺癌细胞的附加生长抑制和凋亡，以及对P21、P27、Fas、Bax和切割的Caspase-8、9、3的上调和Bcl-2的下调的重叠效应。此外，Ad-ING 4-IL-24治疗在无胸腺裸鼠中的A549肺癌皮下（sc）异种移植肿瘤生长和减少A549异种移植肿瘤中的CD 34和微血管密度中具有相加抑制作用。Ad-ING 4-IL-24诱导的抗肿瘤活性增强与外源性和内源性凋亡途径的协同激活以及肿瘤血管生成的叠加抑制密切相关。因此，我们的研究结果表明，癌症基因治疗结合两个或两个以上的肿瘤抑制因子，如ING 4和IL-24可能构成一个新的和有效的治疗策略，肺癌和其他癌症。
ING4 as a member of inhibitor of growth (ING) tumor suppressor family has potent inhibitory effects on a variety of tumors. Interleukin-24 (IL-24), a cytokine-tumor suppressor, also shows broad-spectrum and tumor-specific antitumor activities. In this report, we constructed an ING4/IL-24 bicistronic adenovirus (Ad-ING4-IL-24) and assessed its combined effect on in vitro and in vivo A549 human non-small cell lung cancer cells. We demonstrated that ING4 and IL-24 combination treatment by adenovirus-mediated ING4 and IL-24 coexpression induced additive growth suppression and apoptosis as well as an overlapping effect on upregulation of P21, P27, Fas, Bax and cleaved Caspases-8, 9, 3 and downregulation of Bcl-2 in in vitro A549 lung carcinoma cells. Moreover, Ad-ING4-IL-24 treatment additively inhibited in vivo A549 lung carcinoma subcutaneous (sc) xenografted tumor growth and reduced CD34 and microvessel density in A549 xenografted tumors in athymic nude mice. The enhanced antitumor activity elicited by Ad-ING4-IL-24 was closely associated with the coordinate activation of extrinsic and intrinsic apoptotic pathways and additive inhibition of tumor angiogenesis. Thus, our results indicate that cancer gene therapy combining two or more tumor suppressors such as ING4 and IL-24 may constitute a novel and effective therapeutic strategy for lung carcinoma and other cancers.