Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL.
Aptamer-miRNA-212 Conjugate Sensitizes NSCLC Cells to TRAIL.
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DOI：
10.1038/mtna.2016.5
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发表时间：
2016-03-08
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影响因子：
--
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肿瘤坏死因子相关的凋亡诱导配体(TRAIL)是一种很有前景的抗肿瘤药物，它能选择性地诱导癌细胞凋亡，而不影响健康旁观者细胞的生存能力。TRAIL肿瘤抑制通路在包括肺癌在内的许多人类恶性肿瘤中被解除调控。在人非小细胞肺癌(NSCLC)细胞中，通过增加肿瘤抑制因子microRNA-212(miR-212)的表达水平，从而抑制与耐药有关的抗凋亡蛋白PED/PEA-15的表达，可以恢复对TRAIL治疗的敏感性。在本研究中，我们利用在肺癌细胞上表达的酪氨酸激酶受体Axl(GL21.T)的RNA适体抑制剂，作为一种将miR-212转导到表达Ax1的人NSCLC细胞的手段。我们证明了在miR与GL21.T(GL21.T-miR212嵌合体)接合后有效地递送miR-212。我们发现，嵌合体下调PED并恢复TRAIL介导的癌细胞细胞毒作用。重要的是，用嵌合体治疗Axl+肺癌细胞导致(I)caspase活性增加，(Ii)与TRAIL联合治疗时细胞存活率降低。综上所述，我们证明GL21.T-miR212嵌合体可以作为TRAIL治疗肺癌的佐剂。
TNF-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent for its remarkable ability to selectively induce apoptosis in cancer cells, without affecting the viability of healthy bystander cells. The TRAIL tumor suppressor pathway is deregulated in many human malignancies including lung cancer. In human non-small cell lung cancer (NSCLC) cells, sensitization to TRAIL therapy can be restored by increasing the expression levels of the tumor suppressor microRNA-212 (miR-212) leading to inhibition of the anti-apoptotic protein PED/PEA-15 implicated in treatment resistance. In this study, we exploited a previously described RNA aptamer inhibitor of the tyrosine kinase receptor Axl (GL21.T) expressed on lung cancer cells, as a means to deliver miR-212 into human NSCLC cells expressing Axl. We demonstrate efficient delivery of miR-212 following conjugation of the miR to GL21.T (GL21.T-miR212 chimera). We show that the chimera downregulates PED and restores TRAIL-mediate cytotoxicity in cancer cells. Importantly, treatment of Axl+ lung cancer cells with the chimera resulted in (i) an increase in caspase activation and (ii) a reduction of cell viability in combination with TRAIL therapy. In conclusion, we demonstrate that the GL21.T-miR212 chimera can be employed as an adjuvant to TRAIL therapy for the treatment of lung cancer.
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影响因子：
46.9
作者：
Dassie, Justin P.;Liu, Xiu-ying;Thomas, Gregory S.;Whitaker, Ryan M.;Thiel, Kristina W.;Stockdale, Katie R.;Meyerholz, David K.;McCaffrey, Anton P.;McNamara, James O., II;Giangrande, Paloma H.
通讯作者：
Giangrande, Paloma H.
影响因子：
3.1
作者：
Chung, BI;Malkowicz, SB;McGarvey, TW
通讯作者：
McGarvey, TW
DOI：
10.1007/978-1-4939-3197-2_3
发表时间：
2016-01-01
期刊：
NUCLEIC ACID APTAMERS
影响因子：
--
作者：
Catuogno, Silvia;Esposito, Carla Lucia;de Franciscis, Vittorio
通讯作者：
de Franciscis, Vittorio
DOI：
10.1007/978-0-387-89520-8_1
发表时间：
2009-01-01
期刊：
THERAPEUTIC TARGETS OF THE TNF SUPERFAMILY
影响因子：
--
作者：
Grewal, Iqbal S.
通讯作者：
Grewal, Iqbal S.
影响因子：
6.4
作者：
Garofalo, Michela;Romano, Giulia;Condorelli, Gerolama
通讯作者：
Condorelli, Gerolama