Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin
Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin
复制标题
靶向MIR34C-5p-ATG4B-自噬轴增强宫颈癌细胞对吡柔比星的敏感性
DOI：
10.1080/15548627.2016.1173798
复制
发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Lian, Jiqin
中科院分区：
文献类型：
--
作者：
Wu, Yaran;Ni, Zhenhong;Lian, Jiqin
吡拉西坦（THP）是新一代蒽环类抗癌药物。在临床上，THP和基于THP的联合疗法已被证明对各种肿瘤有效，而没有严重的副作用。然而，既往临床研究表明，大多数宫颈癌患者对THP治疗不敏感，相关机制尚不清楚。与临床研究一致，我们证实了宫颈癌细胞在体外和体内对THP具有抗性。我们的数据表明，THP诱导宫颈癌细胞的保护性巨自噬/自噬反应，抑制这种自噬显着增强THP的细胞毒性。通过扫描自噬相关基因mRNA水平的变化，我们发现自噬相关4 B半胱氨酸肽酶（ATG 4 B）的上调在THP诱导的自噬中起重要作用。此外，THP通过促进mRNA的稳定性而不影响其转录，从而增加了宫颈癌细胞中ATG 4 B的mRNA水平。此外，THP引发MIR 34 C-5 p的下调，这与ATG 4 B和自噬诱导的上调有关。MIR 34 C-5 p的过表达显著降低了ATG 4 B的水平，减弱了自噬，同时增强了THP处理的宫颈癌细胞的细胞死亡和凋亡。这些结果首次揭示了THP处理的宫颈癌细胞中存在MIR 34 C-5 p-ATG 4 B-自噬信号传导轴，并且该轴至少部分地解释了宫颈癌患者中的THP不敏感性。该研究可能为提高THP的化疗效果提供新的见解，这可能有利于THP在宫颈癌治疗中的进一步临床应用。
ABSTRACT Pirarubicin (THP) is a newer generation anthracycline anticancer drug. In the clinic, THP and THP-based combination therapies have been demonstrated to be effective against various tumors without severe side effects. However, previous clinical studies have shown that most patients with cervical cancer are not sensitive to THP treatment, and the associated mechanisms are not clear. Consistent with the clinical study, we confirmed that cervical cancer cells were resistant to THP in vitro and in vivo. Our data demonstrated that THP induced a protective macroautophagy/autophagy response in cervical cancer cells, and suppression of this autophagy dramatically enhanced the cytotoxicity of THP. By scanning the mRNA level change of autophagy-related genes, we found that the upregulation of ATG4B (autophagy-related 4B cysteine peptidase) plays an important role in THP-induced autophagy. Moreover, THP increased the mRNA level of ATG4B in cervical cancer cells by promoting mRNA stability without influencing its transcription. Furthermore, THP triggered a downregulation of MIR34C-5p, which was associated with the upregulation of ATG4B and autophagy induction. Overexpression of MIR34C-5p significantly decreased the level of ATG4B and attenuated autophagy, accompanied by enhanced cell death and apoptosis in THP-treated cervical cancer cells. These results for the first time reveal the presence of a MIR34C-5p-ATG4B-autophagy signaling axis in THP-treated cervical cancer cells in vitro and in vivo, and the axis, at least partially, accounts for the THP nonsensitivity in cervical cancer patients. This study may provide a new insight for improving the chemotherapeutic effect of THP, which may be beneficial to the further clinical application of THP in cervical cancer treatment.