Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1α in vitro
Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1α in vitro
复制标题
熊果酸通过抑制缺氧诱导因子1α的表达下调ABCG2抑制卵巢癌干细胞增殖并逆转耐药性
DOI：
10.3892/or.2016.4813
复制
发表时间：
2016-07-01
期刊：
影响因子：
4.2
通讯作者：
Guo, Piao-Ting
中科院分区：
文献类型：
--
作者：
Wang, Wen-Jing;Sui, Hua;Guo, Piao-Ting
肿瘤缺氧与耐药密切相关。缺氧诱导因子-1 α（HIF-1 alpha）或ABCG 2是否与缺氧诱导的抵抗有关尚未得到证实。熊果酸（UA）与顺铂联合应用可显著增加卵巢癌干细胞（CSCs）对顺铂的敏感性，但其确切机制尚不清楚。使用细胞计数试剂盒-8（CCK-8）在贴壁和球形细胞（SKOV 3、A2780和HEY）中评价顺铂在不同条件下的细胞生长抑制率。采用定量PCR、免疫印迹和免疫荧光法检测不同培养条件下及UA处理后HIF-1 α和ABCG 2的表达。通过shRNA和LY 294002敲低HIF-1 α来抑制PI 3 K/Akt通路的活性。卵巢CSCs表达干细胞相关基因和耐药性明显高于正常贴壁细胞。在低氧条件下，卵巢CSCs比常氧条件下生长更快，更耐药。在不同培养条件下，UA可通过抑制ABCG 2和HIF-1 α来抑制卵巢CSC的增殖并逆转其耐药性。HIF-1 α抑制剂YC-1联合UA可抑制低氧条件下的干细胞基因和ABCG 2。PI 3 K/Akt信号通路激活在UA诱导的HIF-1 α下调和ABCG 2减少中起重要的功能作用。UA通过抑制HIF-1 α和ABCG 2的表达下调来抑制卵巢CSCs的增殖和耐药性逆转。
Hypoxia in tumors is closely related to drug resistance. It has not been verified whether hypoxia-inducible factor-1 alpha (HIF-1 alpha) or ABCG2 is related to hypoxia-induced resistance. Ursolic acid (UA), when used in combination with cisplatin can significantly increase the sensitivity of ovarian cancer stem cells (CSCs) to cisplatin, but the exact mechanism is unknown. The cell growth inhibitory rate of cisplatin under different conditions was evaluated using Cell Counting Kit-8 (CCK-8) in adherence and sphere cells (SKOV3, A2780, and HEY). The expression of HIF-1 alpha and ABCG2 was tested using quantitative PCR, western blotting, and immunofluorescence under different culture conditions and treated with UA. Knockdown of HIF-1 alpha by shRNA and LY294002 was used to inhibit the activity of PI3K/Akt pathway. Ovarian CSCs express sternness-related genes and drug resistance significantly higher than normal adherent cells. Under hypoxic conditions, the ovarian CSCs grew faster and were more drug resistant than under normoxia. UA could inhibit proliferation and reverse the drug resistance of ovarian CSC by suppressing ABCG2 and HIF-1 alpha under different culture conditions. HIF-1 alpha inhibitor YC-1 combined with UA suppressed the sternness genes and ABCG2 under hypoxic condition. The PI3K/Akt signaling pathway activation plays an important functional role in UA-induced downregulation of HIF-1 alpha and reduction of ABCG2. UA inhibits the proliferation and reversal of drug resistance in ovarian CSCs by suppressing the expression of downregulation of HIF-1 alpha and ABCG2.