Evidence that tumor necrosis factor-related apoptosis-inducing ligand induction by 5-Aza-2'-deoxycytidine sensitizes human breast cancer cells to adriamycin.
Evidence that tumor necrosis factor-related apoptosis-inducing ligand induction by 5-Aza-2'-deoxycytidine sensitizes human breast cancer cells to adriamycin.
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DOI：
10.1158/0008-5472.can-06-2310
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发表时间：
2007-02
期刊：
影响因子：
11.2
通讯作者：
Jing Xu;Junhao Zhou;M. Tainsky;Gen Sheng Wu
中科院分区：
文献类型：
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作者：
Jing Xu;Junhao Zhou;M. Tainsky;Gen Sheng Wu
DNA甲基转移酶抑制剂5-氮杂-2‘-脱氧胞苷(5-aza-2’-deoxcytidine，5-aza-CDR)可抑制DNA甲基转移酶的活性，并使癌细胞对化疗增敏，但其增敏机制尚不完全清楚。在此，我们发现5-氮杂环-2-脱氧胞苷(5-aza-cdr)可诱导人乳腺癌MDA-231细胞中肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的表达。5-aza-CDR诱导TRAIL与Akt失活相关。此外，我们发现，腺病毒感染过表达Akt的活性形式或其药物抑制剂抑制Akt下游的目标糖原合成酶激酶3可取消5-aza-CDR对TRAIL的诱导。重要的是，我们发现，与单独使用任何一种药物相比，联合使用5-氮杂胞苷和阿霉素可显著增加乳腺癌细胞的凋亡性死亡。此外，联合治疗同时激活了死亡受体和线粒体的凋亡途径，而阿霉素单独只激活了线粒体途径，而5-aza-cdr两者都没有激活。更重要的是，通过小干扰RNA沉默下调TRAIL的表达，减少了5-aza-CDR介导的阿霉素诱导的caspase激活和细胞凋亡，从而导致阿霉素耐药。综上所述，我们的研究结果表明，5-氮杂-硫代脱氧胞苷诱导TRAIL对于提高乳腺癌细胞对阿霉素的化疗敏感性至关重要。
The DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) inhibits DNA methyltransferase activity and sensitizes cancer cells to chemotherapy, but the mechanisms of its sensitization are not fully understood. Here, we show that 5-aza-CdR induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the human breast cancer MDA-231 cells. Induction of TRAIL by 5-aza-CdR correlated with inactivation of Akt. Furthermore, we show that overexpression of the active form of Akt by adenovirus infection or inhibition of the Akt downstream target glycogen synthase kinase 3 by its pharmacologic inhibitors abolishes TRAIL induction by 5-aza-CdR. Importantly, we show that the combined treatment of breast cancer cells with 5-aza-CdR and Adriamycin significantly increases apoptotic cell death compared with the treatment with either agent alone. Moreover, the combined treatment activated both death receptor and mitochondrial apoptotic pathways, whereas Adriamycin alone activated only the mitochondrial pathway while 5-aza-CdR failed to activate either. More importantly, down-regulation of TRAIL by small interference RNA silencing decreased 5-aza-CdR-mediated Adriamycin-induced caspase activation and apoptosis, thus conferring Adriamycin resistance. Taken together, our results suggest that induction of TRAIL by 5-aza-CdR is critical for enhancing chemosensitivity of breast cancer cells to Adriamycin.