Zhenhan Zhu, Wenxia Jiang, Jiehao Zhou, Alexander Robert Maldeney, Jingru Liang, Jing Yang, Wei Luo
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引用次数: 0
Abstract
Background
The sterol regulatory element-binding protein (SREBP) pathway is essential for maintaining sterol homeostasis during B cell activation and germinal center B cell proliferation. However, its potential as a therapeutic target to treat B-cell lymphoma remains unclear.
Methods
We examined SREBP protein expression in human B-cell lymphoma samples using immunohistochemistry. Additionally, we conducted in vitro studies using SREBP signaling inhibitors in combination with rapamycin to assess their effects on cell proliferation and lipid metabolism in B-cell lymphoma cells.
Results
Our analysis revealed high levels of SREBP2 protein expression in human B-cell lymphoma samples. Inhibiting SREBP signaling or its downstream target HMG-CoA reductase (HMGCR) with Fatostatin or Simvastatin effectively suppressed B-cell lymphoma cell proliferation. However, B-cell lymphoma cells responded to statin treatment by activating the mTORC1-pS6 pathway, suggesting a compensatory mechanism to overcome statin-induced cell cycle arrest. Combining low-dose statin treatment with the mTOR inhibitor rapamycin produced a synergistic effect, significantly inhibiting B-cell lymphoma proliferation, cell cycle progression, and lipid raft formation.
Conclusions
These results highlight the potential of a combined therapeutic approach targeting both SREBP and mTORC1 as a novel strategy for treating B-cell lymphoma.
背景：固醇调节元件结合蛋白（SREBP）通路对于维持B细胞活化和生殖中心B细胞增殖过程中的固醇平衡至关重要。然而，其作为治疗 B 细胞淋巴瘤靶点的潜力仍不清楚：我们使用免疫组化方法检测了人B细胞淋巴瘤样本中SREBP蛋白的表达。此外，我们还使用SREBP信号抑制剂联合雷帕霉素进行了体外研究，以评估它们对B细胞淋巴瘤细胞增殖和脂质代谢的影响：我们的分析发现，人B细胞淋巴瘤样本中SREBP2蛋白表达水平很高。使用法托司汀或辛伐他汀抑制SREBP信号或其下游靶标HMG-CoA还原酶（HMGCR）可有效抑制B细胞淋巴瘤细胞的增殖。然而，B细胞淋巴瘤细胞通过激活mTORC1-pS6通路对他汀类药物治疗做出反应，这表明存在一种克服他汀类药物诱导的细胞周期停滞的补偿机制。将低剂量他汀治疗与mTOR抑制剂雷帕霉素联合使用可产生协同效应，显著抑制B细胞淋巴瘤的增殖、细胞周期进展和脂质筏的形成：这些结果凸显了针对SREBP和mTORC1的联合治疗方法作为治疗B细胞淋巴瘤新策略的潜力。
期刊介绍：
Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas:
Clinical Cancer Research
Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations
Cancer Biology:
Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery.
Cancer Prevention:
Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach.
Bioinformatics:
Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers.
Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.
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