Loss of ARID1A expression leads to sensitivity to ROS-inducing agent elesclomol in gynecologic cancer cells.
Loss of ARID1A expression leads to sensitivity to ROS-inducing agent elesclomol in gynecologic cancer cells.
复制标题
DOI：
10.18632/oncotarget.10921
复制
发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
Wong KK
中科院分区：
文献类型：
--
作者：
Kwan SY;Cheng X;Tsang YT;Choi JS;Kwan SY;Izaguirre DI;Kwan HS;Gershenson DM;Wong KK
ARID 1A的失活突变在广泛的癌症类型中发现，在妇科癌症中频率最高。然而，靶向ARID 1A突变癌细胞的治疗策略仍然有限。在这项研究中，我们的目的是确定ARID 1A突变癌细胞系的药物敏感性。通过分析癌症药物敏感性基因组数据库，我们发现ARID 1A突变癌细胞系对活性氧（ROS）诱导剂elesclomol治疗更敏感。在一组14个妇科癌细胞系中，elesclomol治疗抑制ARID 1A突变细胞的生长并诱导凋亡。RMG 1和OVCA 432卵巢癌细胞中ARID 1A的敲低导致对elesclomol的敏感性增加，而TOV 21 G卵巢癌细胞中ARID 1A表达的恢复导致对elesclomol的耐药性增加。此外，我们发现ARID 1A表达的敲低导致细胞内ROS水平增加。在卵巢透明细胞癌患者样本中，ARID 1A的低表达与8-羟基鸟苷（氧化应激标志物）的高表达相关。总之，我们首次证明了ARID 1A的缺失导致ROS的积累，并表明elesclomol可用于靶向ARID 1A突变型妇科癌细胞。
Inactivating mutations in ARID1A are found in a broad spectrum of cancer types, with the highest frequency in gynecologic cancers. However, therapeutic strategies targeting ARID1A-mutant cancer cells remain limited. In this study, we aimed to identify drugs sensitivities in ARID1A-mutant cancer cell lines. By analyzing the Genomics of Drug Sensitivity in Cancer database, we found that ARID1A-mutant cancer cell lines were more sensitive to treatment with the reactive oxygen species (ROS)-inducing agent elesclomol. In a panel of 14 gynecologic cancer cell lines, treatment with elesclomol inhibited growth and induced apoptosis more potently in ARID1A-mutant cells. Knockdown of ARID1A in RMG1 and OVCA432 ovarian cancer cells resulted in increased sensitivity to elesclomol, whereas restoration of ARID1A expression in TOV21G ovarian cancer cells resulted in increased resistance to elesclomol. Furthermore, we found that knockdown of ARID1A expression resulted in increased intracellular ROS levels. In ovarian clear cell carcinoma patient samples, low expression of ARID1A correlated with high expression of 8-hydroxyguanosine, a marker for oxidative stress. In summary, we demonstrate for the first time that loss of ARID1A leads to accumulation of ROS and suggest that elesclomol may be used to target ARID1A-mutant gynecologic cancer cells.