Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function.
Tubeimoside I induces accumulation of impaired autophagolysosome against cervical cancer cells by both initiating autophagy and inhibiting lysosomal function.
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Tubeimoside I 通过启动自噬和抑制溶酶体功能诱导受损的自噬溶酶体针对宫颈癌细胞的积累
DOI：
10.1038/s41419-018-1151-3
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发表时间：
2018-11-02
影响因子：
9
通讯作者：
Lei Y
中科院分区：
文献类型：
--
作者：
Feng X;Zhou J;Li J;Hou X;Li L;Chen Y;Fu S;Zhou L;Li C;Lei Y
宫颈癌是最具侵袭性的人类癌症之一，由于持续的化疗耐药和反复复发，预后较差。Tubeimoside I （TBM）是一种有效的抗肿瘤药物，通过触发细胞凋亡和诱导细胞周期阻滞来抑制癌细胞增殖。然而，具体的机制尚不清楚，需要进一步阐明，特别是在宫颈癌中。在本研究中，我们发现TBM在体外和体内均可诱导宫颈癌细胞增殖抑制和细胞死亡。进一步的研究结果表明，TBM可以诱导自噬体积累，这对于TBM对抗宫颈癌细胞是重要的。机制研究表明，TBM通过两种途径增加自噬体：首先，TBM通过激活AMPK，使Beclin1- vps34复合物稳定，从而使Bcl-2与Beclin1分离；其次，TBM可损害溶酶体组织蛋白酶活性，阻断自噬通量，导致受损的自噬溶酶体积累。与此一致的是，自噬起始抑制可减轻TBM诱导的细胞死亡，而自噬通量抑制可加重TBM在宫颈癌细胞中的细胞毒活性。值得注意的是，TBM作为一种新型致死性受损自噬溶酶体诱导剂，可能会增强顺铂、紫杉醇等化疗药物对宫颈癌的治疗效果。总之，我们的研究为TBM在抗肿瘤治疗中的分子机制提供了新的见解，并为TBM在宫颈癌治疗中的临床应用奠定了基础。
Cervical cancer is one of the most aggressive human cancers with poor prognosis due to constant chemoresistance and repeated relapse. Tubeimoside I (TBM) has been identified as a potent antitumor agent that inhibits cancer cell proliferation by triggering apoptosis and inducing cell cycle arrest. Nevertheless, the detailed mechanism remains unclear and needs to be further elucidated, especially in cervical cancer. In this study, we found that TBM could induce proliferation inhibition and cell death in cervical cancer cells both in vitro and in vivo. Further results demonstrated that treatment with TBM could induce autophagosome accumulation, which was important to TBM against cervical cancer cells. Mechanism studies showed that TBM increased autophagosome by two pathways: First, TBM could initiate autophagy by activating AMPK that would lead to stabilization of the Beclin1-Vps34 complex via dissociating Bcl-2 from Beclin1; Second, TBM could impair lysosomal cathepsin activity and block autophagic flux, leading to accumulation of impaired autophagolysosomes. In line with this, inhibition of autophagy initiation attenuated TBM-induced cell death, whereas autophagic flux inhibition could exacerbated the cytotoxic activity of TBM in cervical cancer cells. Strikingly, as a novel lethal impaired autophagolysosome inducer, TBM might enhance the therapeutic effects of chemotherapeutic drugs towards cervical cancer, such as cisplatin and paclitaxel. Together, our study provides new insights into the molecular mechanisms of TBM in the antitumor therapy, and establishes potential applications of TBM for cervical cancer treatment in clinic.
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影响因子：
29
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通讯作者：
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