Roles of mTOR and STAT3 in autophagy induced by telomere 3′ overhang-specific DNA oligonucleotides
Roles of mTOR and STAT3 in autophagy induced by telomere 3′ overhang-specific DNA oligonucleotides
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DOI：
10.4161/auto.4602
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发表时间：
2007-09-01
期刊：
影响因子：
13.3
通讯作者：
Kondo, Seiji
中科院分区：
文献类型：
--
作者：
Yokoyama, Tomohisa;Kondo, Yasuko;Kondo, Seiji
端粒3‘端悬垂特异的DNA寡核苷酸(T-寡核苷酸)可能通过模拟端粒环路的破坏而诱导癌细胞死亡，因此被认为是一种有前途的新的治疗策略。我们先前在体内外证明了T-寡核苷酸通过诱导非凋亡性自噬来抑制恶性胶质瘤细胞的增殖。利用反相蛋白质芯片分析和Western blotting，我们发现T-寡核苷酸抑制哺乳动物雷帕霉素靶标(MTOR)和信号转导和转录激活因子3(STAT3)。此外，雷帕霉素(mTOR抑制剂)和AG490(STAT3抑制剂)通过增强自噬作用使恶性胶质瘤细胞对T-寡聚糖敏感。虽然众所周知，mTOR是自噬的负调控因子，但据我们所知，STAT3和自噬之间的关系从未被证明。这些发现表明，通过抑制mTOR和STAT3诱导自噬的新机制，T-寡聚糖有望成为治疗恶性胶质瘤的有效药物。在这里，我们讨论T-寡核苷酸对细胞信号通路的影响的证据，这可能解释了它们通过抑制STAT3和mTOR来刺激自噬的能力。
Telomere 3 ' overhang-specific DNA oligonucleotides (T-oligos) induce cancer cell death, presumably by mimicking telomere loop disruption and are, therefore, considered a promising new therapeutic strategy. We previously demonstrated that T-oligos inhibit the proliferation of malignant glioma cells in vitro and in vivo by inducing non-apoptotic autophagy. Using a reverse-phase protein microarray analysis and Western blotting, we revealed that T-oligos inhibit the mammalian target of rapamycin (mTOR) and the signal transducer and activator of transcription 3 (STAT3). Moreover, rapamycin (mTOR inhibitor) and AG490 (STAT3 inhibitor) sensitize malignant glioma cells to T-oligos by augmenting autophagy. Although mTOR is well known as a negative regulator of autophagy, the relationship between STAT3 and autophagy has never been demonstrated, to our knowledge. These findings suggest that, by exhibiting a novel mechanism of inducing autophagy through inhibition of mTOR and STAT3, T-oligos are a promising therapeutic agent for treating malignant gliomas. Here, we discuss evidence for T-oligos' effects on cell signaling pathways that may explain their ability to stimulate autophagy by inhibiting STAT3 as well as mTOR.