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Endocytic degradation of ErbB2 mediates the effectiveness of neratinib in the suppression of ErbB2-positive ovarian cancer.
The International Journal of Biochemistry & Cell Biology ( IF 3.4 ) Pub Date : 2019-11-02 , DOI: 10.1016/j.biocel.2019.105640
Shanshan Wang 1 , Jinrui Zhang 1 , Taishu Wang 1 , Feng Ren 1 , Xiuxiu Liu 1 , Yongqi Lu 1 , Linying Xu 1 , Yang Zhang 1 , Duchuang Wang 1 , Lu Xu 1 , Yueguang Wu 1 , Fang Liu 1 , Qiong Li 1 , Mohamed Y Zaky 2 , Shuyan Liu 1 , Weijie Dong 3 , Fang Liu 4 , Kun Zou 5 , Yingqiu Zhang 1
Affiliation  

The tyrosine kinase receptor ErbB2 is frequently found to be overexpressed in multiple cancer types. Targeted therapeutic approaches against ErbB2 have shown promising results and received FDA approvals in the treatment of breast cancer. However, this approach has not been granted in ovarian cancers till now. In order to assess the validity of ErbB2-targeted therapy in ovarian cancer, we investigated the effectiveness of two FDA-approved tyrosine kinase inhibitors of ErbB2, lapatinib and neratinib, on the growth of ovarian cancers. We observed that both lapatinib and neratinib displayed inhibitory effects towards the proliferation and migration of ErbB2-positive ovarian cancer cells in vitro, with neratinib showing stronger suppression in general. Neratinib treatment led to the reduction of ErbB2 protein levels, with concomitant attenuation of the phosphorylation of AKT, MEK, and ERK1/2. Immunofluorescence assays revealed that neratinib induced the internalization and lysosomal degradation of ErbB2, which was accompanied by its hyperubiquitylation. Lapatinib and neratinib also repressed the in vivo growth of SKOV3 cells, and neratinib downregulated ErbB2 levels in xenograft tumors to cause potent inhibition. Therefore, the ubiquitylation-mediated endocytic degradation of ErbB2 incurred by neratinib treatment conferred potent inhibition of ovarian cancer growth. Clinical investigations of neratinib in ErbB2-positive ovarian cancer are warranted.



中文翻译:

ErbB2的内吞降解介导了neratinib在抑制ErbB2阳性卵巢癌中的有效性。

经常发现酪氨酸激酶受体ErbB2在多种癌症类型中过表达。针对ErbB2的靶向治疗方法已显示出令人鼓舞的结果,并获得FDA批准用于治疗乳腺癌。但是,到目前为止,这种方法尚未在卵巢癌中得到批准。为了评估针对ErbB2的疗法在卵巢癌中的有效性,我们调查了两种FDA批准的ErbB2酪氨酸激酶抑制剂,拉帕替尼和neratinib对卵巢癌的有效性。我们观察到拉帕替尼和那拉替尼均对ErbB2阳性卵巢癌细胞的增殖和迁移具有抑制作用,而neratinib一般表现出较强的抑制作用。奈拉替尼治疗导致ErbB2蛋白水平降低,并伴随着AKT,MEK和ERK1 / 2磷酸化的减弱。免疫荧光分析显示,neratinib诱导ErbB2的内在化和溶酶体降解,并伴有其高泛素化。Lapatinib和neratinib还抑制了SKOV3细胞的体内生长,并且neratinib下调了异种移植肿瘤中的ErbB2水平,从而产生了有效的抑制作用。因此,由neratinib治疗引起的ErbB2的泛素化介导的内吞降解可有效抑制卵巢癌的生长。neratinib治疗ErbB2阳性卵巢癌的临床研究值得肯定。

更新日期:2019-11-02
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