Timosaponin AIII Induces G2/M Arrest and Apoptosis in Breast Cancer by Activating the ATM/Chk2 and p38 MAPK Signaling Pathways.
Timosaponin AIII Induces G2/M Arrest and Apoptosis in Breast Cancer by Activating the ATM/Chk2 and p38 MAPK Signaling Pathways.
复制标题
Timosaponin AIII 通过激活 ATM/Chk2 和 p38 MAPK 信号通路诱导乳腺癌 G2/M 期停滞和细胞凋亡。
DOI：
10.3389/fphar.2020.601468
复制
发表时间：
2020
影响因子：
5.6
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Zhang M;Qu J;Gao Z;Qi Q;Yin H;Zhu L;Wu Y;Liu W;Yang J;Huang X
刺五加皂苷AIII(TAIII)是一种甾体皂苷，在多种癌症尤其是乳腺癌中具有很强的抗肿瘤活性。然而，TAIII抗乳腺癌的具体分子机制仍不清楚。在这里，我们发现TAIII在体外和体内都会触发DNA损伤，导致G2/M期停滞，并最终诱导乳腺癌细胞凋亡。TAIII诱导MDA-MB-231和MCF7细胞发生G2/M期停滞和凋亡，并下调CyclinB1、CDc2和CDc25C的表达。进一步的数据显示，ATM/Chk2和p38通路被激活，表现为p-H2A.X和p-p38水平的上调，这表明TAIII诱导DNA损伤，导致细胞周期停滞和细胞凋亡。使用ATM和p38通路的抑制剂进一步证实了TAIII的作用。体内实验表明，TAIII对皮下移植瘤生长无明显抑制作用，Ki67和TUNEL检测结果表明，TAIII对皮下移植瘤无明显毒副作用。数据还表明，TAIII在体内激活了ATM/Chk2和p38 MAPK通路，这与体外的作用一致。因此，我们的研究结果表明，TAIII可触发DNA损伤，激活ATM/Chk2和p38MAPK通路，进而诱导乳腺癌细胞发生G2/M期阻滞和细胞凋亡，为TAIII作为抗乳腺癌药物提供了理论依据。
Timosaponin AIII (TAIII), a steroidal saponin, exerts potent anti-tumor activity in various cancers, especially breast cancer. However, the concrete molecular mechanisms of TAIII against breast cancer are still unclear. Here, we find that TAIII triggers DNA damage, leads to G2/M arrest, and ultimately induces apoptosis in breast cancer both in vitro and in vivo. TAIII induced G2/M phase arrest and apoptosis in MDA-MB-231 and MCF7 cells accompanied with down-regulation of CyclinB1, Cdc2 and Cdc25C. Further data showed that the ATM/Chk2 and p38 pathways were activated representing by up-regulated levels of p-H2A.X and p-p38, which indicated an induction of DNA damage by TAIII, leading to cell cycle arrest and apoptosis. The effects of TAIII were further confirmed by employing inhibitors of ATM and p38 pathways. In vivo, TAIII suppressed the growth of subcutaneous xenograft tumor without obvious toxicity, which indicated by Ki67 and TUNEL analysis. Data also showed that TAIII stimulated the ATM/Chk2 and p38 MAPK pathways in vivo, which in consistent with the effects in vitro. Hence, our data demonstrate that TAIII triggers DNA damage and activates ATM/Chk2 and p38 MAPK pathways, and then induces G2/M phase arrest and apoptosis in breast cancer, which provide theoretical evidence for TAIII utilized as drug against breast cancer.
登录
查看更多内容
影响因子：
3.7
作者：
Casagrande, F;Darbon, JM
通讯作者：
Darbon, JM
影响因子：
3.7
作者：
King FW;Fong S;Griffin C;Shoemaker M;Staub R;Zhang YL;Cohen I;Shtivelman E
通讯作者：
Shtivelman E
影响因子：
2.7
作者：
Jung, Okkeun;Lee, Jongsung;Lee, Sang Yeol
通讯作者：
Lee, Sang Yeol
影响因子：
4
作者：
Collins, I;Garrett, MD
通讯作者：
Garrett, MD
影响因子：
64.8
作者：
Downs, JA;Lowndes, NF;Jackson, SP
通讯作者：
Jackson, SP