The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B.
The Downregulation of eIF3a Contributes to Vemurafenib Resistance in Melanoma by Activating ERK via PPP2R1B.
复制标题
eIF3a 的下调通过 PPP2R1B 激活 ERK 导致黑色素瘤中维莫非尼耐药
DOI：
10.3389/fphar.2021.720619
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发表时间：
2021
影响因子：
5.6
通讯作者：
Liu ZQ
中科院分区：
文献类型：
--
作者：
Jiang SL;Wang ZB;Zhu T;Jiang T;Fei JF;Liu C;Luo C;Cheng Y;Liu ZQ
BRAF V600E抑制剂Vemurafenib为黑色素瘤患者提供治疗益处，但耐药性的频繁出现仍然是一个挑战。对远武烯基耐药性基础机制的理解可能会为黑色素瘤患者产生新的治疗策略。在这里，我们表明EIF3A是一种翻译调节蛋白，是参与vemurafenib耐药性的重要介体。在耐维美富尼A375黑色素瘤细胞（A375R）中，EIF3A的表达水平明显低于父母A375细胞。 EIF3A的过表达通过降低P-ERK水平来增强对BRAF抑制剂的敏感性。此外，EIF3A通过翻译机制调节磷酸酶PPP2R1B的表达来控制ERK活性，从而确定了黑色素瘤细胞对vemurafenib的敏感性。此外，在人类蛋白质图集和TCGA数据库的肿瘤样品中，还观察到EIF3A和PPP2R1B表达之间的正相关。总之，我们的研究揭示了BRAF抑制剂耐药性的先前未知的分子机制，这可能为预测临床治疗中的vemurafenib反应提供了新的策略。
Vemurafenib, a BRAF V600E inhibitor, provides therapeutic benefits for patients with melanoma, but the frequent emergence of drug resistance remains a challenge. An understanding of the mechanisms underlying vemurafenib resistance may generate novel therapeutic strategies for patients with melanoma. Here, we showed that eIF3a, a translational regulatory protein, was an important mediator involved in vemurafenib resistance. eIF3a was expressed at significantly lower levels in vemurafenib-resistant A375 melanoma cells (A375R) than in parental A375 cells. Overexpression of eIF3a enhanced the sensitivity to BRAF inhibitors by reducing p-ERK levels. Furthermore, eIF3a controlled ERK activity by regulating the expression of the phosphatase PPP2R1B via a translation mechanism, thus determining the sensitivity of melanoma cells to vemurafenib. In addition, a positive correlation between eIF3a and PPP2R1B expression was also observed in tumor samples from the Human Protein Atlas and TCGA databases. In conclusion, our studies reveal a previously unknown molecular mechanism of BRAF inhibitor resistance, which may provide a new strategy for predicting vemurafenib responses in clinical treatment.
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影响因子：
6.3
作者：
Kim A;Cohen MS
通讯作者：
Cohen MS
影响因子：
64.8
作者：
Boussemart, Lise;Malka-Mahieu, Helene;Vagner, Stephan
通讯作者：
Vagner, Stephan
影响因子：
6.4
作者：
Bellmann, Lydia;Cappellano, Giuseppe;Stoitzner, Patrizia
通讯作者：
Stoitzner, Patrizia
影响因子：
3.7
作者：
Dong, Zizheng;Liu, Zhaoqian;Zhang, Jian-Ting
通讯作者：
Zhang, Jian-Ting
DOI：
10.1007/978-3-319-91442-8_6
发表时间：
2018-01-01
期刊：
Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer
影响因子：
--
作者：
Garbe, Claus;Eigentler, Thomas K
通讯作者：
Eigentler, Thomas K