Granato Marisa, Rizzello Celeste, Gilardini Montani Maria Saveria, Cuomo Laura, Vitillo Marina, Santarelli Roberta, Gonnella Roberta, D'Orazi Gabriella, Faggioni Alberto, Cirone Mara
Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
U. O.C. Patologia Clinica, Ospedale San Filippo Neri, 00135 Rome, Italy.
J Nutr Biochem. 2017 Mar;41:124-136. doi: 10.1016/j.jnutbio.2016.12.011. Epub 2017 Jan 5.
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/β-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 PI3K/AKT/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.
槲皮素是日常食用的多种蔬菜中所含的一种生物类黄酮，长期以来一直因其抗炎和抗癌特性而受到研究。槲皮素与多种癌症相关通路相互作用，如PI3K/AKT、Wnt/β-连环蛋白和STAT3。这些通路在原发性渗出性淋巴瘤（PEL）中被过度激活，原发性渗出性淋巴瘤是一种侵袭性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了PEL细胞中的PI3K/AKT/mTOR和STAT3通路，因此，它下调了存活相关细胞蛋白如c-FLIP、细胞周期蛋白D1和c-Myc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，槲皮素在这些细胞中诱导了存活自噬，并增强了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肿瘤发生的潜伏和裂解KSHV蛋白的表达，并上调了HLA-DR和钙网蛋白的表面表达，使死亡细胞更有可能被免疫系统检测到。本研究获得的结果表明，槲皮素对正常B细胞不具有任何细胞毒性，可能是治疗这种侵袭性B细胞淋巴瘤的良好候选药物，特别是与自噬抑制剂或硼替佐米联合使用时。
