Deregulation of Exo70 Facilitates Innate and Acquired Cisplatin Resistance in Epithelial Ovarian Cancer by Promoting Cisplatin Efflux.
Deregulation of Exo70 Facilitates Innate and Acquired Cisplatin Resistance in Epithelial Ovarian Cancer by Promoting Cisplatin Efflux.
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Exo70 的失调通过促进顺铂流出促进上皮性卵巢癌的先天性和获得性顺铂耐药
DOI：
10.3390/cancers13143467
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发表时间：
2021-07-11
期刊：
影响因子：
5.2
通讯作者：
Hu T
中科院分区：
文献类型：
--
作者：
Zhao Y;Hong X;Chen X;Hu C;Lu W;Xie B;Zhong L;Zhang W;Cao H;Chen B;Liu Q;Zhan Y;Xiao L;Hu T
先天和获得性铂耐药是上皮性卵巢癌（EOC）死亡的主要原因。然而，其机制仍然难以捉摸。在这里，我们发现Exo70，一个囊胞的关键亚基，在EOC中上调，促进顺铂外排，促进先天耐药。更有趣的是，顺铂可以下调Exo70以维持细胞敏感性。然而，长时间的顺铂治疗阻碍了这一功能，从而稳定了Exo70，促进了EOC细胞获得性顺铂耐药性。我们的研究增强了Exo70作为克服EOC顺铂耐药的有希望的靶点。虽然研究阐明了多种细胞内机制，但铂耐药上皮性卵巢癌（EOC）仍然是卵巢癌治疗的主要挑战。在这里，我们报道Exo70，一个囊泡复合物的关键亚基，有助于EOC的先天和获得性顺铂耐药。在EOC组织中观察到Exo70的上调，并与EOC患者的铂耐药和无进展生存有关。Exo70通过促进胞吐介导的顺铂外排抑制EOC细胞对顺铂的敏感性。此外，顺铂通过调节AMPK和mTOR的磷酸化诱导自噬-溶酶体降解Exo70蛋白，从而降低细胞耐药性。然而，在长时间的顺铂治疗过程中，功能受到阻碍，这反过来又稳定了Exo70，促进了EOC细胞获得性顺铂耐药。在体外和体内，敲低Exo70或通过Exo70抑制剂Endosidin2抑制胞吐，可逆转EOC细胞的顺铂耐药。我们的研究结果表明，通过增加顺铂外排，Exo70过表达和过度稳定有助于先天和获得性顺铂耐药，靶向Exo70可能是EOC治疗中克服顺铂耐药的一种方法。
Innate and acquired platinum resistance are the leading causes of epithelial ovarian cancer (EOC) mortality. However, the mechanisms remain elusive. Here we found that Exo70, a key subunit of the exocyst, is upregulated in EOC and promotes cisplatin efflux to facilitate innate resistance. More interestingly, cisplatin could downregulate Exo70 to sustain cell sensitivity. However, this function was hampered during prolonged cisplatin treatment, which in turn stabilized Exo70 to facilitate the acquired cisplatin resistance of EOC cells. Our study potentiates Exo70 as a promising target to overcome cisplatin resistance in EOC. Whilst researches elucidating a diversity of intracellular mechanisms, platinum-resistant epithelial ovarian cancer (EOC) remains a major challenge in the treatment of ovarian cancer. Here we report that Exo70, a key subunit of the exocyst complex, contributes to both innate and acquired cisplatin resistance of EOC. Upregulation of Exo70 is observed in EOC tissues and is related to platinum resistance and progression-free survival of EOC patients. Exo70 suppressed the cisplatin sensitivity of EOC cells through promoting exocytosis-mediated efflux of cisplatin. Moreover, cisplatin-induced autophagy-lysosomal degradation of Exo70 protein by modulating phosphorylation of AMPK and mTOR, thereby reducing the cellular resistance. However, the function was hampered during prolonged cisplatin treatment, which in turn stabilized Exo70 to facilitate the acquired cisplatin resistance of EOC cells. Knockdown of Exo70, or inhibiting exocytosis by Exo70 inhibitor Endosidin2, reversed the cisplatin resistance of EOC cells both in vitro and in vivo. Our results suggest that Exo70 overexpression and excessive stability contribute to innate and acquired cisplatin resistance through the increase in cisplatin efflux, and targeting Exo70 might be an approach to overcome cisplatin resistance in EOC treatment.
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DOI：
10.1042/bj20081359
发表时间：
2009-04-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Dolgova NV;Olson D;Lutsenko S;Dmitriev OY
通讯作者：
Dmitriev OY
影响因子：
1.8
作者：
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通讯作者：
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DOI：
10.1016/j.ogc.2019.07.003
发表时间：
2019-12-01
影响因子：
3.2
作者：
Froyman, Wouter;Timmerman, Dirk
通讯作者：
Timmerman, Dirk
影响因子：
3.3
作者：
Liu, Jianglan;Zuo, Xiaofeng;Guo, Wei
通讯作者：
Guo, Wei
影响因子：
3.8
作者：
Kalayda GV;Wagner CH;Buss I;Reedijk J;Jaehde U
通讯作者：
Jaehde U