Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway
Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway
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Bufadienolide 化合物通过抑制 STAT3/Mcl-1 通路使人乳腺癌细胞对 TRAIL 诱导的细胞凋亡敏感
DOI：
10.1007/s10495-011-0573-5
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发表时间：
2011-04-01
期刊：
影响因子：
7.2
通讯作者：
Hu, Hongbo
中科院分区：
文献类型：
--
作者：
Dong, Yinhui;Yin, Shutao;Hu, Hongbo
死亡受体配体TRAIL由于其对恶性细胞的优先毒性而被认为是癌症治疗的有希望的候选者。然而，它的功效受到了许多耐药机制的挑战。因此，需要能够克服抗性以增强TRAIL的治疗功效的药剂。在本研究中，我们发现蟾毒灵、蟾毒他林和γ蟾毒他林（蟾毒二烯内酯的关键成员，从传统中药蟾酥中分离）显著增强ER-α不同状态的人乳腺癌细胞对TRAIL的凋亡诱导，如增强Annexin V/FITC阳性细胞（凋亡细胞）、细胞质组蛋白相关DNA片段、膜通透性转换（MPT）、半胱天冬酶活化和PARP裂解。进一步的机制研究表明蟾毒灵能够显著降低Mcl-1的表达，并适度降低Bcl-XL的表达水平。这些抗凋亡蛋白的下调与转录因子STAT 3激活的抑制密切相关。通过敲低或过表达Mcl-1的方法证实了蟾蜍灵与TRAIL结合的增强作用中下调Mcl-1的重要结果。我们的发现首次提供了强有力的证据，蟾蜍二烯类化合物具有良好的潜力，被开发为一类新的TRAIL的敏化剂。
The death receptor ligand TRAIL is considered a promising candidate for cancer therapy because of its preferential toxicity to malignant cells. However its efficacy has been challenged by a number of resistance mechanisms. Therefore, agents that can overcome the resistance to enhance therapeutic efficacy of TRAIL are needed. In the current study, we found that bufalin, bufotalin and gamabufotalin, key members of bufadienolides isolated from a traditional Chinese medicine ChanSu, significantly potentiated human breast cancer cells with different status of ER-alpha to apoptosis induction of TRAIL, as evidenced by enhanced Annexin V/FITC positive cells (apoptotic cells), cytoplasmic histone-associated-DNA-fragments, membrane permeability transition (MPT), caspases activation and PARP cleavage. Further mechanistic investigation demonstrated that bufalin was able to significantly decrease Mcl-1 expression and modestly decrease Bcl-XL expression level. Down-regulations of these anti-apoptotic proteins were well correlated with inhibition of transcription factor STAT3 activation. The important consequence of down-regulation Mcl-1 in the enhancement action by combining bufalin with TRAIL was confirmed by either knockdown or overexpression of Mcl-1 approach. Our findings for the first time provided strong evidences that bufadienolide compounds have excellent potential to be developed as a novel class of sensitizers of TRAIL.