Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan.
Gynecol Oncol. 2015 Jun;137(3):538-45. doi: 10.1016/j.ygyno.2015.03.053. Epub 2015 Apr 1.
The anti-malarial drug chloroquine (CQ) is also known as an autophagy inhibitor. Autophagy can promote tumor growth by fueling the necessary energy metabolism and inducing resistance to chemotherapy and/or irradiation in various human cancers. However, the role of autophagy in endometrial cancer has not yet been established. We investigated the anti-tumor effects and autophagy inhibition caused by CQ in endometrial cancer cells.
Cell proliferation and cell cycle were assessed in response to CQ in six endometrial cancer cell lines by using an MTT assay and/or flow cytometry. To assess the level of autophagy, western blotting and an immunofluorescence assay were used to measure LC3 expression. The effects of knockdown of either ATG5 or ATG7, both of which are indispensable for induction of autophagy, were assessed via an MTT assay. Sensitivity to CQ was compared between parental and cisplatin-resistant (CP-r) Ishikawa endometrial cancer cells.
CQ suppressed proliferation in all six endometrial cancer cell lines in a dose-dependent manner, whereas it increased the population of apoptotic cells. Inhibition of autophagy via knockdown of either ATG5 or ATG7 decreased the sensitivity to CQ. Additionally, sensitivity to cisplatin was improved by knocking down ATG5 or ATG7. Finally, CP-r Ishikawa cells, with a high basal level of autophagy, were more sensitive to CQ than parental Ishikawa cells.
Our data suggest that autophagy is involved in endometrial tumor growth and cisplatin resistance. Furthermore, our data support a therapeutic role for CQ in endometrial cancer cells with upregulation of autophagy.
抗疟药物氯喹（CQ）也被称为自噬抑制剂。自噬可以通过为各种人类癌症的必要能量代谢提供燃料并诱导对化疗和/或放疗的抗性来促进肿瘤生长。然而，自噬在子宫内膜癌中的作用尚未确定。我们研究了 CQ 对子宫内膜癌细胞的抗肿瘤作用和自噬抑制作用。
通过 MTT 测定法和/或流式细胞术，在六种子宫内膜癌细胞系中评估 CQ 对细胞增殖和细胞周期的影响。为了评估自噬水平，使用 Western blot 和免疫荧光测定法测量 LC3 表达。通过 MTT 测定法评估 ATG5 或 ATG7 敲低（两者对于诱导自噬都是必不可少的）的作用。比较亲本和顺铂耐药（CP-r）Ishikawa 子宫内膜癌细胞对 CQ 的敏感性。
CQ 以剂量依赖性方式抑制所有六种子宫内膜癌细胞系的增殖，而增加凋亡细胞的群体。通过敲低 ATG5 或 ATG7 抑制自噬会降低对 CQ 的敏感性。此外，敲低 ATG5 或 ATG7 可提高顺铂的敏感性。最后，具有高基础自噬水平的 CP-r Ishikawa 细胞比亲本 Ishikawa 细胞对 CQ 更敏感。
我们的数据表明自噬参与子宫内膜肿瘤生长和顺铂耐药。此外，我们的数据支持 CQ 在自噬上调的子宫内膜癌细胞中具有治疗作用。
