Targeting G6PD reverses paclitaxel resistance in ovarian cancer by suppressing GSTP1
Targeting G6PD reverses paclitaxel resistance in ovarian cancer by suppressing GSTP1
复制标题
靶向 G6PD 通过抑制 GSTP1 逆转卵巢癌中的紫杉醇耐药性
DOI：
10.1016/j.bcp.2020.114092
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发表时间：
2020-08-01
影响因子：
5.8
通讯作者：
Shan, Changliang
中科院分区：
文献类型：
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作者：
Feng, Qi;Li, Xiuru;Shan, Changliang
卵巢癌是全球女性死亡的主要原因之一。紫杉醇是目前最有效的化疗药物之一。然而，紫杉醇耐药是治疗失败的主要原因，紫杉醇耐药的确切机制仍不清楚。在这项研究中，我们证明了氧化戊糖磷酸途径（PPP）酶葡萄糖-6-磷酸脱氢酶（G6 PD）促进紫杉醇耐药性。我们发现G6 PD在紫杉醇耐药癌细胞中的表达高于紫杉醇敏感癌细胞。此外，我们证明了使用shRNA或抑制剂作为单一药物或组合抑制G6 PD，使紫杉醇耐药癌细胞对紫杉醇治疗敏感，从而提高紫杉醇的治疗效果。有趣的是，我们发现紫杉醇耐药细胞中G6 PD的上调是由于蛋白质精氨酸甲基转移酶6（PRMT 6）的表达减少，其靶向G6 PD的启动子。我们进一步确定，G6 PD通过调节谷胱甘肽S-转移酶P1（GSTP 1）的表达促进紫杉醇耐药性，GSTP 1通过解毒几种抗癌药物而赋予对化疗的耐药性。综上所述，我们的研究结果表明，G6 PD是一个新的潜在的目标，以克服紫杉醇耐药。
Ovarian cancer is one of the leading causes of mortality in women worldwide. Currently, paclitaxel is one of the most effective chemotherapies. However, resistance to paclitaxel is a major cause of therapy failure and the precise mechanism of paclitaxel resistance remains unclear. In this study, we demonstrated that the oxidative pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) promotes paclitaxel resistance. We showed that G6PD expression was higher in paclitaxel-resistant cancer cells than in their paclitaxel-sensitive counterparts. Furthermore, we demonstrated that suppressing G6PD using shRNA, or an inhibitor, either as single agents or in combination, sensitized paclitaxel-resistant cancer cells to paclitaxel treatment and thereby improving the therapeutic efficacy of paclitaxel. Interestingly, we found that the upregulation of G6PD in paclitaxel-resistant cells was due to the decreased expression of protein arginine methyltransferase 6 (PRMT6), which targets the promoter of G6PD. We further identified that G6PD promotes paclitaxel resistance by regulating the expression of glutathione S-transferase P1 (GSTP1), which confers resistance to chemotherapy by detoxifying several anticancer drugs. Taken together, our results suggest that G6PD is a novel potential target to overcome paclitaxel resistance.