Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, PR China.
Department of Biochemistry and Molecular Biology, Shreveport, LA 71130-3932, USA; Department of Hematology and Oncology, Shreveport, LA 71130-3932, USA; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
Biochem Pharmacol. 2022 Aug;202:115139. doi: 10.1016/j.bcp.2022.115139. Epub 2022 Jun 11.
Therapeutically targeting B cells has received great attention in the treatment of B-cell malignancies and autoimmune diseases. The B-cell activating factor (BAFF) is critical to the survival of normal and neoplastic B cells, and excess production of BAFF contributes to autoimmune diseases. Resveratrol, a natural polyphenolic compound, has a positive effect on the treatment of autoimmune diseases. However, how resveratrol affects BAFF-stimulated B-cell proliferation and survival is poorly understood. Here, we show that resveratrol increased autophagosome formation and ATG5/LC3-II levels and decreased p62 level, promoting autophagic flux/autophagy and thereby suppressing the basal or human soluble BAFF (hsBAFF)-stimulated proliferation and survival of normal and B-lymphoid (Raji) cells. This is supported by the findings that inhibition of autophagy with 3-methyladenine (3-MA, an inhibitor of Vps34) or ATG5 shRNA attenuates resveratrol-induced autophagy and -reduced proliferation/viability in B-cells. Inhibition of mTOR with rapamycin or knockdown of mTOR potentiated resveratrol-induced autophagy and inhibition of hsBAFF-stimulated B-cell proliferation/viability, while overexpression of wild-type mTOR conferred resistance to the actions of resveratrol. Similarly, inhibition of Akt with Akt inhibitor X or ectopic expression of dominant negative Akt reinforced resveratrol-induced autophagy and inhibition of hsBAFF-stimulated B-cell proliferation/viability, whereas expression of constitutively active Akt conferred resistance to the actions of resveratrol. Taken together, these results indicate that resveratrol induces autophagy impeding BAFF-stimulated proliferation and survival via blocking the Akt/mTOR signaling pathway in normal and neoplastic B cells. Our findings highlight that resveratrol has a great potential for prevention and treatment of excessive BAFF-elicited aggressive B-cell disorders and autoimmune diseases.
靶向 B 细胞治疗在 B 细胞恶性肿瘤和自身免疫性疾病的治疗中受到了极大的关注。B 细胞激活因子（BAFF）对正常和肿瘤 B 细胞的存活至关重要，BAFF 过量产生导致自身免疫性疾病。白藜芦醇是一种天然多酚化合物，对自身免疫性疾病的治疗有积极作用。然而，白藜芦醇如何影响 BAFF 刺激的 B 细胞增殖和存活尚不清楚。在这里，我们发现白藜芦醇增加了自噬体的形成和 ATG5/LC3-II 的水平，并降低了 p62 的水平，促进了自噬流/自噬，从而抑制了基础或人可溶性 BAFF（hsBAFF）刺激的正常和 B 淋巴细胞（Raji）细胞的增殖和存活。这一发现得到了以下结果的支持：用 3-甲基腺嘌呤（3-MA，Vps34 的抑制剂）或 ATG5 shRNA 抑制自噬会减弱白藜芦醇诱导的自噬，并减少 B 细胞中的增殖/活力；用雷帕霉素抑制 mTOR 或敲低 mTOR 会增强白藜芦醇诱导的自噬和抑制 hsBAFF 刺激的 B 细胞增殖/活力，而过表达野生型 mTOR 会使白藜芦醇的作用产生抗性。同样，用 Akt 抑制剂 X 抑制 Akt 或过表达显性失活 Akt 会增强白藜芦醇诱导的自噬和抑制 hsBAFF 刺激的 B 细胞增殖/活力，而表达组成型激活 Akt 会使白藜芦醇的作用产生抗性。综上所述，这些结果表明，白藜芦醇通过阻断 Akt/mTOR 信号通路在正常和肿瘤 B 细胞中诱导自噬，从而抑制 BAFF 刺激的增殖和存活。我们的研究结果表明，白藜芦醇在预防和治疗过度 BAFF 诱导的侵袭性 B 细胞疾病和自身免疫性疾病方面具有很大的潜力。
