Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells.
Synergy between RA and TLR3 promotes type I IFN-dependent apoptosis through upregulation of TRAIL pathway in breast cancer cells.
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DOI：
10.1038/cddis.2013.5
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发表时间：
2013-01-31
影响因子：
9
通讯作者：
Jimenez-Lara, A. M.
中科院分区：
文献类型：
--
作者：
Bernardo, A. R.;Cosgaya, J. M.;Aranda, A.;Jimenez-Lara, A. M.
关键词：
由于其能够调节癌细胞的生长、分化和凋亡，视黄酸（RA）被认为是在肿瘤学中具有前景的治疗潜力的信号分子。在这项研究中，我们表明，RA是能够诱导乳腺癌细胞的内在能力，识别双链RNA（dsRNA）通过上调Toll样受体3（TLR 3）的表达。RA与dsRNA模拟物聚肌苷酸-聚胞苷酸（poly（I：C））共同施用，协同作用以建立能够通过同时上调TLR 3、dsRNA解旋酶黑色素瘤分化相关抗原-5（MDA-5）和RA诱导基因-1（RIG-1）以及dsRNA活化蛋白激酶（PKR）表达来感测dsRNA的特异性应答程序，导致乳腺癌细胞特异性表达dsRNA传感器的下游转录靶标，例如干扰素-β（IFNβ）、白介素-8（IL-8）、趋化因子（C-C基序）配体5（CCL 5）和C-X-C基序趋化因子10（CXCL 10）。RA和poly（I：C）共处理也诱导TLR 3依赖性凋亡程序，其与肿瘤坏死因子（TNF）相关的凋亡诱导配体（TRAIL）的诱导相关，并有助于阻断乳腺癌细胞增殖。RA/poly（I：C）诱导乳腺癌细胞凋亡的机制涉及I型IFN自分泌信号、caspase-8和caspase-3激活以及TRAIL信号。我们的研究结果揭示了RA，TLR 3和TRAIL之间的重要联系，并强调了RA和poly（I：C）的组合使用作为一种潜在的有效的肿瘤治疗方法，通过改善对合成dsRNA的作用具有低敏感性的癌细胞的凋亡反应。
Due to its ability to regulate the growth, differentiation and apoptosis of cancer cells, retinoic acid (RA) is considered a signaling molecule with promising therapeutic potential in oncology. In this study, we show that RA is able to induce the intrinsic ability of breast cancer cells to recognize double-stranded RNA (dsRNA) through the upregulation of Toll-like receptor 3 (TLR3) expression. RA, co-administered with the dsRNA mimicker polyinosinic–polycytidylic acid (poly(I:C)), synergizes to mount a specific response program able to sense dsRNA through the concurrent upregulation of TLR3, the dsRNA helicases melanoma differentiation-associated antigen-5 (MDA-5) and RA-inducible gene-1 (RIG-1), and the dsRNA-activated protein kinase (PKR) expression, leading breast cancer cells to specifically express downstream transcriptional targets of dsRNA sensors, such as interferon-β (IFNβ), interleukin-8 (IL-8), chemokine (C-C motif) ligand 5 (CCL5), and C-X-C motif Chemokine 10 (CXCL10). A TLR3-dependent apoptotic program is also induced by RA and poly(I:C) co-treatment that correlates with the induction of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and contributes to block breast cancer cell proliferation. The mechanisms of apoptosis induced by RA/poly(I:C) in breast cancer cells involve type I IFN autocrine signaling, caspase-8 and caspase-3 activation, as well as TRAIL signaling. Our results reveal important links among RA, TLR3 and TRAIL and highlight the combined use of RA and poly(I:C) as a potential effective tumor therapy by improving the apoptotic response of cancer cells with low sensitivity to the action of synthetic dsRNA.
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影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
3.9
作者：
Jiang, Qun;Wei, Haiming;Tian, Zhigang
通讯作者：
Tian, Zhigang
影响因子：
4.8
作者：
Kolla, V;Lindner, DJ;Kalvakolanu, DV
通讯作者：
Kalvakolanu, DV
影响因子：
6.4
作者：
Chen, QY;Ma, YF;Ross, AC
通讯作者：
Ross, AC
DOI：
10.1097/ppo.0b013e3181eaca65
发表时间：
2010-07
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
--
作者：
Gnjatic S;Sawhney NB;Bhardwaj N
通讯作者：
Bhardwaj N