Tumor growth suppression by inhibiting both autophagy and STAT3 signaling in HNSCC.
Tumor growth suppression by inhibiting both autophagy and STAT3 signaling in HNSCC.
复制标题
通过抑制 HNSCC 中的自噬和 STAT3 信号传导来抑制肿瘤生长。
DOI：
10.18632/oncotarget.6294
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发表时间：
2015-12-22
期刊：
影响因子：
--
通讯作者：
Sun ZJ
中科院分区：
文献类型：
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作者：
Fan TF;Bu LL;Wang WM;Ma SR;Liu JF;Deng WW;Mao L;Yu GT;Huang CF;Liu B;Zhang WF;Sun ZJ
自噬被认为是一把双刃剑。它可以延长癌细胞的生存时间并增强其对细胞凋亡的抵抗力，而矛盾的是，缺陷性自噬与肿瘤发生的增加有关，但这种现象背后的机制尚不清楚。在这项研究中，我们证明了信号转导和转录激活因子3（p-STAT 3）的磷酸化减少与通过Akt/mTOR和Erk信号通路在人头颈部鳞状细胞癌（HNSCC）中增加的自噬相关。我们还表明，通过NSC 74859阻断STAT 3可以显著诱导凋亡性细胞死亡和自噬。同时，增加的自噬抑制细胞凋亡。自噬和STAT 3的药理学或遗传学抑制进一步使HNSCC细胞对凋亡敏感。此外，来自异种移植模型的证据证明，抑制STAT 3活性与抑制自噬相结合促进肿瘤消退优于单独的任一种治疗。综上所述，本研究表明，自噬加剧了HNSCC中的凋亡细胞死亡，NSC 74859抑制STAT 3和自噬的组合可能是HNSCC有希望的新治疗策略。
Autophagy is considered as a double-edged sword. It can prolong the survival of cancer cells and enhance its resistance to apoptosis, and paradoxically, defective autophagy has been linked to increased tumorigenesis, but the mechanism behind this phenomenon is unclear. In this study, we demonstrated that decreased phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) was correlated with increased autophagy through the Akt/mTOR and Erk signaling pathways in human head and neck squamous cell carcinoma (HNSCC). We also showed that blockage of STAT3 by NSC74859 could markedly induce apoptotic cell death and autophagy. Meanwhile, increased autophagy inhibited apoptosis. The pharmacological or genetic inhibition of autophagy and STAT3 further sensitized HNSCC cells to apoptosis. Furthermore, evidence from xenograft model proved that suppressed STAT3 activity combined with inhibition of autophagy promoted tumor regression better than either treatment alone. Taken together, this present study demonstrated that autophagy alleviates apoptotic cell death in HNSCC, and combination of inhibition of STAT3 by NSC74859 and autophagy might be a promising new therapeutic strategy for HNSCC.