Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer.
Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer.
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DOI：
10.1016/j.jhep.2015.04.018
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发表时间：
2015-09
影响因子：
25.7
通讯作者：
Thorgeirsson SS
中科院分区：
文献类型：
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作者：
Marquardt JU;Gomez-Quiroz L;Arreguin Camacho LO;Pinna F;Lee YH;Kitade M;Domínguez MP;Castven D;Breuhahn K;Conner EA;Galle PR;Andersen JB;Factor VM;Thorgeirsson SS
癌症干细胞（cancer stem cells，CSCs）对包括肝细胞癌（hepatocellular carcinoma，HCC）在内的多重耐药癌症具有重要的治疗意义。在肝CSC中频繁激活的关键途径之一是NF-kB信号传导。我们评估了通过IKK抑制剂姜黄素、RNAi和特异性肽SN 50实现的肝癌中NF-κ B抑制的CSC消耗潜力。通过分析侧群（SP）、球体形成和致瘤性来评估对CSC的影响。通过RT-qPCR、全局基因表达微阵列、EMSA和Western印迹法确定分子变化。暴露于姜黄素的HCC细胞系对姜黄素表现出不同的反应，并被分类为敏感和耐药。在敏感株系中，姜黄素介导的细胞死亡诱导与NF-κ B抑制的程度直接相关。治疗还导致选择性CSC消耗，如通过SP大小减小、球体形成减少、CSC标志物下调和致瘤性抑制所证明的。类似地，通过SN 50和针对p65的siRNA抑制NF-kB抑制肿瘤细胞生长。相反，姜黄素耐药细胞的增殖和CSC标志物的表达表现出矛盾的增加。从机制上讲，姜黄素的CSC消耗活性的一个重要组成部分可以归因于NF-κ B介导的HDAC抑制。共同施用I/II类HDAC抑制剂阿伐他汀使抗性细胞对姜黄素敏感。此外，姜黄素敏感性的预测特征与人HCC数据库的整合表明，具有不良预后和祖细胞特征的HCC最有可能受益于NF-κ B抑制。这些结果表明，阻断NF-kB可以特异性靶向CSC群体，并表明联合抑制NF-kB和HDAC信号传导用于治疗预后不良的肝癌患者的潜力。
The cancer stem cells (CSCs) have important therapeutic implications for multi-resistant cancers including hepatocellular carcinoma (HCC). Among the key pathways frequently activated in liver CSCs is NF-kB signaling. We evaluated the CSCs-depleting potential of NF-kB inhibition in liver cancer achieved by the IKK inhibitor curcumin, RNAi and specific peptide SN50. The effects on CSCs were assessed by analysis of Side Population (SP), sphere formation and tumorigenicity. Molecular changes were determined by RT-qPCR, global gene expression microarray, EMSA, and Western blotting. HCC cell lines exposed to curcumin exhibited differential responses to curcumin and were classified as sensitive and resistant. In sensitive lines, curcumin-mediated induction of cell death was directly related to the extent of NF-kB inhibition. The treatment also led to a selective CSC-depletion as evidenced by a reduced SP size, decreased sphere formation, down-regulation of CSC markers and suppressed tumorigenicity. Similarly, NF-kB inhibition by SN50 and siRNA against p65 suppressed tumor cell growth. In contrast, curcumin-resistant cells displayed a paradoxical increase in proliferation and expression of CSC markers. Mechanistically, an important component of the CSC-depleting activity of curcumin could be attributed to a NF-kB-mediated HDAC inhibition. Co-administration of the class I/II HDAC inhibitor trichostatine sensitized resistant cells to curcumin. Further, integration of a predictive signature of curcumin sensitivity with human HCC database indicated that HCCs with poor prognosis and progenitor features are most likely to benefit from NF-kB inhibition. These results demonstrate that blocking NF-kB can specifically target CSC populations and suggest a potential for combined inhibition of NF-kB and HDAC signaling for treatment of liver cancer patients with poor prognosis.