Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways
Quercetin induces apoptosis and autophagy in primary effusion lymphoma cells by inhibiting PI3K/AKT/mTOR and STAT3 signaling pathways
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DOI：
10.1016/j.jnutbio.2016.12.011
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发表时间：
2017-03-01
影响因子：
5.6
通讯作者：
Cirone, Mara
中科院分区：
文献类型：
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作者：
Granato, Marisa;Rizzello, Celeste;Cirone, Mara
槲皮素是一种生物活性物质，广泛存在于日常食用的蔬菜中，具有抗癌、降血脂等作用。槲皮素与多种癌症相关途径相互作用，例如PI 3 K/AKT、Wnt/il-连环蛋白和STAT 3。这些途径在原发性渗出性淋巴瘤（PEL）中被过度激活，PEL是一种侵袭性B细胞淋巴瘤，其发病机制与致癌病毒卡波西肉瘤相关疱疹病毒（KSHV）密切相关。在本研究中，我们发现槲皮素抑制PEL细胞中的P13 K/AICT/mTOR和STAT 3通路，从而下调促生存细胞蛋白如c-FLIP、cyclin D1和cMyc的表达。它还减少了IL-6和IL-10细胞因子的释放，导致PEL细胞死亡。此外，槲皮素诱导这些细胞中的促生存自噬，并增加蛋白酶体抑制剂硼替佐米对它们的细胞毒性作用。有趣的是，槲皮素还降低了参与PEL肿瘤发生的潜伏性和溶解性KSHV蛋白的表达，并上调了HLA-DR和钙网蛋白的表面表达，使免疫系统更容易检测到垂死细胞。在这项研究中获得的结果表明，槲皮素，它不发挥任何细胞毒性对正常的B细胞，可能是一个很好的候选人治疗这种侵略性B细胞淋巴瘤，特别是在与自噬抑制剂或硼替佐米。(C)2016 Elsevier Inc. All rights reserved.
Quercetin, a bioflavonoid contained in several vegetables daily consumed, has been studied for long time for its antiinflammatory and anticancer properties. Quercetin interacts with multiple cancer-related pathways such as PI3K/AKT, Wnt/il-catenin and STAT3. These pathways are hyperactivated in primary effusion lymphoma (PEL), an aggressive B cell lymphoma whose pathogenesis is strictly linked to the oncogenic virus Kaposis' Sarcoma-associated Herpesvirus (KSHV). In this study, we found that quercetin inhibited P13K/AICT/mTOR and STAT3 pathways in PEL cells, and as a consequence, it down-regulated the expression of the prosurvival cellular proteins such as c-FLIP, cyclin D1 and cMyc. It also reduced the release of IL-6 and IL-10 cytokines, leading to PEL cell death. Moreover, quercetin induced a prosurvival autophagy in these cells and increased the cytotoxic effect of bortezomib, a proteasomal inhibitor, against them. Interestingly, quercetin decreased also the expression of latent and lytic KSHV proteins involved in PEL tumorigenesis and up-regulated the surface expression of HLA-DR and calreticulin, rendering the dying cells more likely detectable by the immune system. The results obtained in this study indicate that quercetin, which does not exert any cytotoxicity against normal B cells, may represent a good candidate for the treatment of this aggressive B cell lymphoma, especially in combination with autophagy inhibitors or with bortezomib. (C) 2016 Elsevier Inc. All rights reserved.