Rhus coriaria induces senescence and autophagic cell death in breast cancer cells through a mechanism involving p38 and ERK1/2 activation.
Rhus coriaria induces senescence and autophagic cell death in breast cancer cells through a mechanism involving p38 and ERK1/2 activation.
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DOI：
10.1038/srep13013
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发表时间：
2015-08-12
影响因子：
4.6
通讯作者：
Iratni R
中科院分区：
文献类型：
--
作者：
El Hasasna H;Athamneh K;Al Samri H;Karuvantevida N;Al Dhaheri Y;Hisaindee S;Ramadan G;Al Tamimi N;AbuQamar S;Eid A;Iratni R
在这里，我们研究了漆树对三种乳腺癌细胞系的抗癌作用。我们证明，漆树乙醇提取物（RCE）抑制这些细胞系的增殖在时间和浓度依赖性的方式。RCE诱导细胞衰老，细胞周期阻滞于G1期。这些变化与p21蛋白表达上调、cyclin D1、p27、PCNA、c-myc、磷酸化RB和衰老相关β-半乳糖苷酶活性表达下调有关。RCE去除后未检测到增殖恢复。膜联蛋白V染色和PARP裂解分析显示，在MDA-MB-231细胞中诱导最小的凋亡。电子显微镜观察发现RCE处理的细胞中存在自噬空泡。有趣的是，通过3-甲基腺嘌呤（3-MA）或氯喹（CQ）阻断自噬减少了RCE诱导的细胞死亡和衰老。RCE还被发现激活p38和ERK 1/2信号通路，这与诱导自噬相一致。此外，我们发现，虽然两种自噬抑制剂都能消除p38磷酸化，但只有CQ导致pERK 1/2显著降低。最后，RCE诱导DNA损伤和减少突变型p53，这两个事件发生在自噬之前。我们的研究结果提供了强有力的证据，R。马桑通过诱导衰老和自噬性细胞死亡而具有强的抗乳腺癌活性，使其成为抗乳腺癌的有希望的替代或辅助治疗候选物。
Here, we investigated the anticancer effect of Rhus coriaria on three breast cancer cell lines. We demonstrated that Rhus coriaria ethanolic extract (RCE) inhibits the proliferation of these cell lines in a time- and concentration-dependent manner. RCE induced senescence and cell cycle arrest at G1 phase. These changes were concomitant with upregulation of p21, downregulation of cyclin D1, p27, PCNA, c-myc, phospho-RB and expression of senescence-associated β-galactosidase activity. No proliferative recovery was detected after RCE removal. Annexin V staining and PARP cleavage analysis revealed a minimal induction of apoptosis in MDA-MB-231 cells. Electron microscopy revealed the presence of autophagic vacuoles in RCE-treated cells. Interestingly, blocking autophagy by 3-methyladenine (3-MA) or chloroquine (CQ) reduced RCE-induced cell death and senescence. RCE was also found to activate p38 and ERK1/2 signaling pathways which coincided with induction of autophagy. Furthermore, we found that while both autophagy inhibitors abolished p38 phosphorylation, only CQ led to significant decrease in pERK1/2. Finally, RCE induced DNA damage and reduced mutant p53, two events that preceded autophagy. Our findings provide strong evidence that R. coriaria possesses strong anti-breast cancer activity through induction of senescence and autophagic cell death, making it a promising alternative or adjunct therapeutic candidate against breast cancer.