Melatonin and andrographolide synergize to inhibit the colospheroid phenotype by targeting Wnt/beta-catenin signaling.
Melatonin and andrographolide synergize to inhibit the colospheroid phenotype by targeting Wnt/beta-catenin signaling.
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DOI：
10.1111/jpi.12808
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发表时间：
2022-08
影响因子：
10.3
通讯作者：
中科院分区：
文献类型：
--
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β-catenin信号传导和血管生成与类colospheroid （CSC）的发育有关。csc是源自结肠癌细胞的球形细胞，与转移、耐药和疾病复发有关。β-连环蛋白失调和抑制血管生成是否会降低CSC生长尚不清楚。在这项研究中，我们利用褪黑激素（MLT）和穿心莲内酯（AGP）的新组合来评估CSC生长抑制的分子机制。这些药物具有抗癌、抗氧化和抗转移的特性。从两种转移性结肠癌细胞系（HT29和HCT-15）中获得CSCs。采用FDA PI染色和免疫印迹检测CD44、CD133、Nanog、Sox2和Oct4细胞的活力和干性。联合用药通过增加ROS水平、降低线粒体膜电位和ATP水平协同降低干性。MLT+AGP通过抑制β-catenin表达及其下调信号Cyclin D1、c-Myc诱导细胞死亡。MLT+AGP处理的细胞表现出磷酸化β-catenin易位到细胞核和去磷酸化-β-catenin。在双重治疗中发现β-catenin激活及其转录因子（TCF4、LEF1）和GTP结合/ g蛋白相关活性下调。血管生成抑制与VEGF mRNA转录物（VEGF189）下调、VEGF受体蛋白磷酸化表达、基质侵袭和毛细血管抑制一致。在体内，静脉注射MLT+AGP可减缓HT29转移性结肠癌。组织病理学显示微血管密度和肿瘤指数明显降低。免疫组化检测caspase 7和β-catenin发现凋亡增加，β-catenin信号下调。其机制是Wnt/β-catenin通路受到抑制。我们的结果为MLT联合AGP抑制crc提供了理论依据。
β-catenin signaling, and angiogenesis are associated with colospheroid (CSC), development. CSCs, spheroids derived from colon cancer cells, are responsible for metastasis, drug resistance, and disease recurrence. Whether dysregulating β-catenin and inhibiting angiogenesis reduces CSC growth is unknown. In this study, the molecular mechanism of CSC growth inhibition was evaluated using a novel combination of melatonin (MLT) and andrographolide (AGP). These drugs have anti-carcinogenic, antioxidant, and anti-metastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT-15). The viability and stemness were monitored (FDA PI staining and immunoblot for CD44, CD133, Nanog, Sox2 and Oct4). The drug combination synergistically diminished stemness via increased ROS levels, reduced mitochondrial membrane potential and ATP level. MLT+AGP induced cell death by inhibiting β-catenin expression and its downregulatory signals, Cyclin D1, c-Myc. MLT+AGP treated cells exhibited translocation of phospho-β-catenin to the nucleus and de-phosphorylated-β-catenin. Downregulation of β-catenin activation and its transcription factors (TCF4, LEF1) and GTP binding/G-protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF mRNA transcripts (VEGF189), phosphorylated VEGF receptor protein expression, matrigel invasion, and capillary tube inhibition. In vivo, the intravenous injection of MLT+AGP slowed HT29 metastatic colon cancer. Histopathology indicated significant reduction in microvascular density and tumor index. Immunohistochemistry for caspase 7, and β-catenin found increased apoptosis and downregulation of β-catenin signals. The mechanism(s) of decreased colospheroids growth were the inhibition of the Wnt/β-catenin pathway. Our results provide rationale for using MLT in combination with AGP for inhibition of CRCs.
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影响因子：
11
作者：
Cheng CC;Liao PN;Ho AS;Lim KH;Chang J;Su YW;Chen CG;Chiang YW;Yang BL;Lin HC;Chang YC;Chang CC;Chang YF
通讯作者：
Chang YF
影响因子：
3.7
作者：
Nacev BA;Liu JO
通讯作者：
Liu JO
影响因子：
78.5
作者：
Bjerkvig, R;Tysnes, BB;Terzis, AJA
通讯作者：
Terzis, AJA
影响因子：
23.9
作者：
Kelly, Kevin F.;Ng, Deborah Y.;Doble, Bradley W.
通讯作者：
Doble, Bradley W.
影响因子：
64.8
作者：
KIM, KJ;LI, B;FERRARA, N
通讯作者：
FERRARA, N