G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells
G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells
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G-四联体配体 SYUIQ-5 通过端粒损伤和 TRF2 离域诱导癌细胞自噬
DOI：
10.1158/1535-7163.mct-09-0244
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发表时间：
2009-12
期刊：
影响因子：
--
通讯作者：
Lian-Quan Gu
中科院分区：
文献类型：
--
作者：
Rong Deng;Gong-Kan Feng;Xiao-Feng Zhu;Wen-Jun Zhou;Xiao-Yue Zhang;Lian-Quan Gu
稳定g -四联体的药物有可能破坏端粒的功能结构，因此可以作为抗肿瘤药物。我们之前报道过SYUIQ-5可以稳定g -四重体，诱导衰老，抑制c-myc基因启动子活性。在本研究中，我们发现SYUIQ-5抑制CNE2和HeLa癌细胞的增殖，引发快速有效的端粒DNA损伤反应，其特征是端粒灶γ-H2AX的形成，并明显诱导自噬，其特征是LC3-II升高，YFP-LC3荧光呈间断模式。这些现象可能主要依赖于TRF2从端粒脱位，而端粒被蛋白酶体进一步降解。此外，TRF2过表达抑制syuiq -5诱导的γ-H2AX表达。同样，在SYUIQ-5处理后，ATM被激活。ATM抑制剂ku55933和ATM siRNA预处理能有效降低γ-H2AX和LC3-II的生成。ATM敲除可部分拮抗SYUIQ-5的抗癌作用。此外，短发夹RNA对自噬相关基因ATG5的自噬抑制可以减弱SYUIQ-5的细胞毒性。这些结果表明，SYUIQ-5通过TRF2从端粒脱位引发端粒损伤，最终诱导癌细胞自噬细胞死亡。我们的发现揭示了SYUIQ-5抗肿瘤作用的新机制。[j]；8 (12): 3203 - 13)
Agents stabilizing G-quadruplexes have the potential to destroy the functional structure of telomere and could therefore act as antitumor agents. We previously reported that SYUIQ-5 could stabilize G-quadruplex, induce senescence, and inhibit c-myc gene promoter activity. In this study, we showed that SYUIQ-5 inhibited proliferation of CNE2 and HeLa cancer cells, triggered a rapid and potent telomere DNA damage response characterized by the formation of telomeric foci γ-H2AX, and obviously induced autophagy with the features of increased LC3-II and a punctuated pattern of YFP-LC3 fluorescence. These phenomena may primarily depend on the delocalization of TRF2 from telomere, which was further degraded by proteasomes. Furthermore, overexpression of TRF2 inhibited SYUIQ-5–induced γ-H2AX expression. Also, ATM was activated following SYUIQ-5 treatment. The pretreatment with ATM inhibitor ku55933 and ATM siRNA effectively reduced the production of γ-H2AX and LC3-II. ATM knockdown partially antagonized the anticancer effects of SYUIQ-5. Moreover, inhibition of autophagy by short hairpin RNA against the autophagy-related gene ATG5 attenuated the cytotoxicity of SYUIQ-5. These results indicated that SYUIQ-5 triggered potent telomere damage through TRF2 delocalization from telomeres, and eventually induced autophagic cell death in cancer cells. Our findings exhibit a novel mechanism that is responsible for the antitumor effects of SYUIQ-5. [Mol Cancer Ther 2009;8(12):3203–13]
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影响因子：
2.9
作者：
Fedoroff, OY;Salazar, M;Hurley, LH
通讯作者：
Hurley, LH
DOI：
10.1083/jcb.152.4.657
发表时间：
2001-02-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mizushima N;Yamamoto A;Hatano M;Kobayashi Y;Kabeya Y;Suzuki K;Tokuhisa T;Ohsumi Y;Yoshimori T
通讯作者：
Yoshimori T
抗癌药物诱导细胞凋亡过程中 c-Jun-NH2 末端激酶通路介导的乙酰胆碱酯酶表达
影响因子：
8
作者：
Deng, R.;Li, W.;Zhu, X-F
通讯作者：
Zhu, X-F
影响因子：
7.3
作者：
Sun, DY;Thompson, B;Hurley, LH
通讯作者：
Hurley, LH
影响因子：
30.8
作者：
Broccoli, D;Smogorzewska, A;deLange, T
通讯作者：
deLange, T