Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction.
Identification of HMGCR as the anticancer target of physapubenolide against melanoma cells by in silico target prediction.
复制标题
通过计算机靶点预测将 HMGCR 鉴定为大毒芋内酯抗黑色素瘤细胞的抗癌靶点。
DOI：
10.1038/s41401-021-00745-x
复制
发表时间：
2022-06
影响因子：
8.2
通讯作者：
Cheng, Yan
中科院分区：
文献类型：
--
作者：
Wang, Hai-yan;Yu, Pian;Chen, Xi-sha;Wei, Hui;Cao, Shi-jie;Zhang, Meng;Zhang, Yi;Tao, Yong-guang;Cao, Dong-sheng;Qiu, Feng;Cheng, Yan
酸浆（Physapubenetrine，PB）是从传统草药小酸浆（Physalis minima L.）中提取的睡茄内酯型化合物，已被证明对癌细胞具有显著的细胞毒性;然而，其分子机制仍不清楚。在这项研究中，我们证明PB通过诱导细胞凋亡抑制黑色素瘤细胞的增殖和迁移。PB的抗癌活性在黑色素瘤异种移植模型中得到进一步验证。为了探索PB抗癌作用的机制，我们进行了一项结合三种方法的计算机靶点预测研究（化学相似性搜索、定量构效关系（QSAR）和分子对接）来鉴定PB的靶点，并且发现PB可能靶向3-羟基-甲基戊二酰CoA还原酶（HMGCR），其为甲羟戊酸途径的限速酶，其促进癌细胞增殖、迁移和转移。我们进一步证明PB与黑色素瘤细胞中的HMGCR相互作用，降低其蛋白表达并抑制HMGCR/雅普通路。此外，我们发现PB可以恢复维罗非尼耐药A-375细胞对维罗非尼的敏感性，这与HMGCR的下调有关。总之，我们证明PB通过靶向HMGCR增强抗癌作用并增强对维罗非尼的敏感性。
Physapubenolide (PB), a withanolide-type compound extracted from the traditional herb Physalis minima L., has been demonstrated to exert remarkable cytotoxicity against cancer cells; however, its molecular mechanisms are still unclear. In this study, we demonstrated that PB inhibited cell proliferation and migration in melanoma cells by inducing cell apoptosis. The anticancer activity of PB was further verified in a melanoma xenograft model. To explore the mechanism underlying the anticancer effects of PB, we carried out an in silico target prediction study, which combined three approaches (chemical similarity searching, quantitative structure-activity relationship (QSAR), and molecular docking) to identify the targets of PB, and found that PB likely targets 3-hydroxy-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, which promotes cancer cell proliferation, migration, and metastasis. We further demonstrated that PB interacted with HMGCR, decreased its protein expression and inhibited the HMGCR/YAP pathway in melanoma cells. In addition, we found that PB could restore vemurafenib sensitivity in vemurafenib-resistant A-375 cells, which was correlated with the downregulation of HMGCR. In conclusion, we demonstrate that PB elicits anticancer action and enhances sensitivity to vemurafenib by targeting HMGCR.
登录
查看更多内容
影响因子：
14.9
作者：
Davies M;Nowotka M;Papadatos G;Dedman N;Gaulton A;Atkinson F;Bellis L;Overington JP
通讯作者：
Overington JP
影响因子：
28.5
作者：
Andriani F;Majorini MT;Mano M;Landoni E;Miceli R;Facchinetti F;Mensah M;Fontanella E;Dugo M;Giacca M;Pastorino U;Sozzi G;Delia D;Roz L;Lecis D
通讯作者：
Lecis D
影响因子：
2.2
作者：
Rutkowski, Robert;Chrzanowski, Robert;Reszec, Joanna
通讯作者：
Reszec, Joanna
影响因子：
4.6
作者：
Ma T;Fan BY;Zhang C;Zhao HJ;Han C;Gao CY;Luo JG;Kong LY
通讯作者：
Kong LY
影响因子：
5.8
作者：
Hamad, Sabri;Adornetto, Gianluca;Campillos, Monica
通讯作者：
Campillos, Monica