Granato Marisa, Rizzello Celeste, Romeo Maria Anele, Yadav Shivangi, Santarelli Roberta, D'Orazi Gabriella, Faggioni Alberto, Cirone Mara
Department of Experimental Medicine, "Sapienza" University of Rome, Italy.
Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy; Department of Medical, Oral and Biotechnological Sciences, University "G. d'Annunzio", Chieti, Italy.
Int J Biochem Cell Biol. 2016 Oct;79:393-400. doi: 10.1016/j.biocel.2016.09.006. Epub 2016 Sep 9.
Burkitt's lymphoma is an aggressive B cell lymphoma whose pathogenesis involves mainly c-Myc translocation and hyperexpression, in addition to antigen-independent BCR signaling and, in some cases, EBV infection. As result of BCR signaling activation, the PI3K/AKT/mTOR pathway results constitutively activated also in the absence of EBV, promoting cell survival and counterbalancing the pro-apoptotic function that c-Myc may also exert. In this study we found that quercetin, a bioflavonoid widely distributed in plant kingdom, reduced c-Myc expression and inhibited the PI3K/AKT/mTOR activity in BL, leading to an apoptotic cell death. We observed a higher cytotoxic effect against the EBV-negative BL cells in comparison with the positive ones, suggesting that this oncogenic gammaherpesvirus confers an additional resistance to the quercetin treatment. Besides cell survival, PI3K/AKT/mTOR pathway also regulates autophagy: we found that quercetin induced a complete autophagic flux in BL cells, that contributes to c-Myc reduction in some of these cells. Indeed, autophagy inhibition by chloroquine partially restored c-Myc expression in EBV-positive (Akata) and EBV-negative (2A8) cells that harbor c-Myc mutation. Interestingly, chloroquine did not affect the quercetin-mediated reduction of c-Myc expression in Ramos cells, that have no c-Myc mutation in the coding region, although autophagy was induced. These results suggest that mutant c-Myc could be partially degraded through autophagy in BL cells, as previously reported for other mutant oncogenic proteins.
伯基特淋巴瘤是一种侵袭性B细胞淋巴瘤，其发病机制主要涉及c-Myc易位和过表达，此外还包括抗原非依赖性BCR信号传导，在某些情况下还涉及EBV感染。由于BCR信号激活，PI3K/AKT/mTOR通路在没有EBV的情况下也会持续激活，促进细胞存活并抵消c-Myc可能发挥的促凋亡功能。在本研究中，我们发现槲皮素，一种广泛分布于植物界的生物类黄酮，可降低BL细胞中c-Myc的表达并抑制PI3K/AKT/mTOR活性，导致细胞凋亡死亡。我们观察到，与EBV阳性细胞相比，槲皮素对EBV阴性BL细胞具有更高的细胞毒性作用，这表明这种致癌性γ疱疹病毒赋予了对槲皮素治疗的额外抗性。除了细胞存活外，PI3K/AKT/mTOR通路还调节自噬：我们发现槲皮素在BL细胞中诱导了完整的自噬流，这在其中一些细胞中有助于降低c-Myc的表达。事实上，用氯喹抑制自噬可部分恢复携带c-Myc突变的EBV阳性（Akata）和EBV阴性（2A8）细胞中c-Myc的表达。有趣的是，氯喹并不影响槲皮素介导的Ramos细胞中c-Myc表达的降低，Ramos细胞在编码区没有c-Myc突变，尽管诱导了自噬。这些结果表明，突变型c-Myc可能在BL细胞中通过自噬被部分降解，正如之前对其他突变致癌蛋白的报道一样。
