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首页> 外文期刊>Archives of Toxicology >Regulation of SIRT1/AMPK axis is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in hepatocellular carcinoma cells
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Regulation of SIRT1/AMPK axis is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in hepatocellular carcinoma cells

机译：SIRT1 / AMPK轴的调节均涉及Gallotannin诱导的衰老和受损的自噬导致肝细胞癌细胞中的细胞死亡

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Hepatocellular carcinoma (HCC) is one of the most fatal malignancies with high mortality worldwide. Here the underlying antitumor mechanism of gallotannin was elucidated in HCC cells. Gallotannin suppressed viability and colony formation, increased subG(1) portion and also induced senescence via upregulation of p21, G(0)/G(1) arrest and higher SA-beta-gal activity in HepG2 and SK-Hep1 cells. However, pan-caspase inhibitor Z-VAD-FMK reversed the ability of gallotannin to activate caspase 3 at 48 h after treatment in two HCC cells. Of note, gallotannin also induced autophagic features by increasing LC3 punctae, LC3B-II conversion, autophagic vacuoles and decreasing the expression of Beclin1 in two HCC cells. Furthermore, autophagy flux assay using GFP-mRFP-LC3 plasmid revealed increased yellowish color and late autophagy inhibitor CQ or NH4Cl enhanced cytotoxicity, LC3B-II conversion, and LC3 punctae in gallotannin-treated HepG2 and SK-Hep1 cells compared to early autophagy inhibitor 3-MA or wortmannin. Interestingly, gallotannin attenuated the expression of SIRT1 and mTOR and activated phosphorylation of AMPK in two HCC cells. Furthermore, AMPK activator AICAR significantly enhanced SA-beta-gal activity and antiproliferation induced by gallotannin, while AMPK inhibitor compound C did not in two HCC cells. Consistently, LC3B-II conversion by gallotannin was not shown in AMPK alpha 1(-/-) MEF cells compared to WT AMPK(+/+) MEF cells. Consistently, gallotannin reduced in vivo growth of HepG2 cells implanted in NCr nude mice along with decreased expression of PCNA and SIRT1 and increased AMPK alpha 1 and TUNEL. Overall, these findings highlight evidence that regulation of SIRT1/AMPK is critically involved in gallotannin-induced senescence and impaired autophagy leading to cell death in HCC cells.
机译：肝细胞癌（HCC）是全世界死亡率高的最致命恶性肿瘤之一。这里，在HCC细胞中阐明了Gallotannin的底层抗肿瘤机制。加兰突抑制了活力和菌落形成，增加了Subg（1）部分，也通过Upregulatual诱导了HepG2和SK-Hep1细胞中的P21，G（0）/ g（1）停滞和更高的SA-Beta-Gal活性的衰老。然而，Pan-Caspase抑制剂Z-VAD-FMK反转了GallotAnnin在两个HCC细胞中处理后48小时激活Caspase 3的能力。值得注意的是，通过增加LC3斑点，LC3B-II转化，自噬液压，减少两种HCC细胞中的BECLIN1的表达，加仑ann也诱导自噬特征。此外，使用GFP-MRFP-LC3质粒的自噬通量测定显示出增加的淡黄色和晚期自噬抑制剂CQ或NH 4CL增强的细胞毒性，LC3B-II转化和LC3泪蛋白，与早期自噬抑制剂3相比，Galtannin治疗的HepG2和SK-Hep1细胞中-MA或Wortmannin。有趣的是，加兰突抑制了SIRT1和MTOR的表达，并在两个HCC细胞中激活了AMPK的磷酸化。此外，AMPK活化剂AICAR显着增强了通过Gallotannin诱导的SA-Beta-Gal活性和抗溶剂，而AMPK抑制剂化合物C不在两个HCC细胞中。与WT AMPK（+ / +）MEF细胞相比，在AMPKα1（ - / - ）MEF细胞中，LC3B-II转化在AMPKα1（ - / - ）MEF细胞中未显示。始终如一地，加仑ann植入在NCR裸鼠中植入的HepG2细胞的体内生长以及PCNA和SIRT1的表达降低，并增加了AMPKα1和TUNEL。总体而言，这些发现突出了SIRT1 / AMPK的调节统治性涉及Gallot annin诱导的衰老和受损的自噬导致HCC细胞中的细胞死亡。

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