NK007 helps in mitigating paclitaxel resistance through p38MAPK activation and HK2 degradation in ovarian cancer
NK007 helps in mitigating paclitaxel resistance through p38MAPK activation and HK2 degradation in ovarian cancer
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DOI：
10.1002/jcp.28278
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发表时间：
2019-09-01
影响因子：
5.6
通讯作者：
Yang, Hengwen
中科院分区：
文献类型：
--
作者：
Li, Zhenhua;Tang, Xin;Yang, Hengwen
卵巢癌对现有药物的耐药性是一个巨大的挑战，急需解决方案，这使得其复发率和死亡率进一步加剧。从天然产物中筛选药物是克服耐药性的一个有前途的方法。在这里，我们报告说，NK 007，（+/-）-山楂碱苹果酸酯从萝摩科分离，选择性抑制A2780和A2780（紫杉醇）细胞的增殖和紫杉醇敏感和耐药卵巢癌细胞的迁移。有趣的是，细胞活力的下降，包括细胞增殖，克隆性和迁移能力是独立于细胞凋亡。在分子水平上，NK 007显著诱导G1/S期阻滞，并上调磷酸化p38丝裂原活化蛋白激酶（p-p38 MAPK）的表达。此外，在存在NK 007的情况下，己糖激酶2（HK 2）蛋白降解显著增加，这导致耗氧速率和胞外酸化速率降低。总之，我们的研究结果表明，NK 007，一个类似物的雷公藤甲素，可以克服紫杉醇（PTX）耐药性通过p38 MAPK激活和HK 2降解。作为一种有效的替代性抗耐药药物，NK 007显示出治疗PTX耐药卵巢癌的潜力。
Ovarian cancer resistance to available medicines is a huge challenge in dire need of a solution, which makes its recurrence and mortality rate further exacerbated. A promising approach to overcome chemoresistance is drug screening from natural products. Here, we report that NK007, a (+/-)-tylophorine malate isolated from the Asclepiadaceae family, selectively inhibited the proliferation of A2780 and A2780 (Taxol) cells and migration of paclitaxel-sensitive and -resistant ovarian cancer cells. Interestingly, the decline of cell viability, including cell multiplication, clonality, and migration capacity was independent on cell apoptosis. At the molecular level, NK007 considerably induced G1/S arrest and upregulated the expression of phospho-p38 mitogen-activated protein kinase (p-p38MAPK). In addition, hexokinase 2 (HK2) protein degradation was considerably elevated in the presence of NK007, which resulted in the reduction of oxygen consumption rate and extracellular acidification rate. Altogether, our results indicate that NK007, an analog of tylophorine, can overcome paclitaxel (PTX) resistance through p38MAPK activation and HK2 degradation. As an effective, alternative antiresistance agent, NK007 exhibits a promising potential to treat PTX-resistant ovarian cancer.