Norcantharidin overcomes vemurafenib resistance in melanoma by inhibiting pentose phosphate pathway and lipogenesis via downregulating the mTOR pathway.
Norcantharidin overcomes vemurafenib resistance in melanoma by inhibiting pentose phosphate pathway and lipogenesis via downregulating the mTOR pathway.
复制标题
去甲斑蝥素通过抑制戊糖磷酸途径和下调 mTOR 途径抑制脂肪生成来克服黑色素瘤中的维莫非尼耐药性
DOI：
10.3389/fphar.2022.906043
复制
发表时间：
2022
影响因子：
5.6
通讯作者：
Liu, Ji-Wei
中科院分区：
文献类型：
--
作者：
Wang, Lei;Otkur, Wuxiyar;Wang, Aman;Wang, Wen;Lyu, Yitong;Fang, Lei;Shan, Xiu;Song, Mingzhou;Feng, Yan;Zhao, Yi;Piao, Hai-Long;Qi, Huan;Liu, Ji-Wei
关键词：
黑色素瘤是最具侵袭性的皮肤癌，发病率高，存活率低。超过一半的黑色素瘤存在BRAF激活突变，其中V600E突变占70%-90%。Vemurafenib （Vem）是一种经fda批准的小分子激酶抑制剂，可选择性靶向活化的BRAF V600E并抑制其活性。然而，大多数接受Vem治疗的患者会产生获得性耐药性。因此，本研究旨在探索一种新的治疗策略来克服Vem耐药性。在这里，我们发现一种潜在的抗癌药物去甲斑蝥素（NCTD）对抗vem黑色素瘤细胞（A375R）的增殖抑制作用比亲本黑色素瘤细胞（A375）更显著，有望成为治疗BRAF v600e突变和获得性抗vem黑色素瘤的药物。代谢组学分析表明，NCTD尤其能逆转Vem抗性导致的戊糖磷酸途径上调和脂肪生成。此外，转录组学分析显示，在NCTD治疗后，A375R细胞中与脂质代谢和哺乳动物雷帕霉素（mTOR）信号通路相关的基因显著下调，而A375细胞中没有。此外，NCTD上调了在调节t细胞应答中起重要作用的嗜丁酸蛋白（butyrophilin， BTN）家族基因。与此一致的是，我们发现Vem耐药导致p-mTOR表达明显升高，而NCTD治疗可以显著降低p-mTOR表达。综上所述，NCTD可能作为解决Vem耐药问题的一种有希望的治疗选择，并通过与免疫调节治疗相结合来改善患者的预后。
Melanoma is the most aggressive type of skin cancer with a high incidence and low survival rate. More than half of melanomas present the activating BRAF mutations, along which V600E mutant represents 70%–90%. Vemurafenib (Vem) is an FDA-approved small-molecule kinase inhibitor that selectively targets activated BRAF V600E and inhibits its activity. However, the majority of patients treated with Vem develop acquired resistance. Hence, this study aims to explore a new treatment strategy to overcome the Vem resistance. Here, we found that a potential anticancer drug norcantharidin (NCTD) displayed a more significant proliferation inhibitory effect against Vem-resistant melanoma cells (A375R) than the parental melanoma cells (A375), which promised to be a therapeutic agent against BRAF V600E-mutated and acquired Vem-resistant melanoma. The metabolomics analysis showed that NCTD could, especially reverse the upregulation of pentose phosphate pathway and lipogenesis resulting from the Vem resistance. In addition, the transcriptomic analysis showed a dramatical downregulation in genes related to lipid metabolism and mammalian target of the rapamycin (mTOR) signaling pathway in A375R cells, but not in A375 cells, upon NCTD treatment. Moreover, NCTD upregulated butyrophilin (BTN) family genes, which played important roles in modulating T-cell response. Consistently, we found that Vem resistance led to an obvious elevation of the p-mTOR expression, which could be remarkably reduced by NCTD treatment. Taken together, NCTD may serve as a promising therapeutic option to resolve the problem of Vem resistance and to improve patient outcomes by combining with immunomodulatory therapy.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
5.7
作者：
Feng Y;Pathria G;Heynen-Genel S;Jackson M;James B;Yin J;Scott DA;Ronai ZA
通讯作者：
Ronai ZA
影响因子：
28.2
作者：
Cantor JR;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
8.8
作者：
Delgado-Goni, Teresa;Galobart, Teresa Casals;Beloueche-Babari, Mounia
通讯作者：
Beloueche-Babari, Mounia
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y