Research progress in the involvement of lipid metabolism in the pathogenesis of multiple myeloma
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摘要: 多发性骨髓瘤是一种常见的血液系统恶性肿瘤，其特征是骨髓中出现异常克隆浆细胞。多发性骨髓瘤的病因尚不清楚，因此，其治疗仍面临极大挑战。最近的研究表明，脂质代谢与多发性骨髓瘤的发生发展密切相关。脂肪酸、胆固醇、前列腺素和磷脂等脂质通过诱导内质网应激、促进细胞凋亡和调控信号通路的表达参与多发性骨髓瘤的发生和发展。因此，靶向脂质代谢可以为多发性骨髓瘤提供一种很有前途的治疗策略。文章重点综述脂质代谢在多发性骨髓瘤发生发展中的作用机制及潜在靶点。Abstract: Multiple myeloma is a common hematologic malignancy characterized by the presence of abnormal clonal plasma cells in the bone marrow. The cause of multiple myeloma is unknown, and as a result, its treatment remains extremely challenging. Recent studies have shown that lipid metabolism is closely related to the development of multiple myeloma. Lipids such as fatty acids, cholesterol, prostaglandins and phospholipids are involved in the development and progression of multiple myeloma by inducing endoplasmic reticulum stress, promoting apoptosis, and modulating the expression of signaling pathways. Therefore, targeting lipid metabolism could provide a promising therapeutic strategy for multiple myeloma. This article focuses on a review of the mechanisms and potential targets of lipid metabolism in the development of multiple myeloma.
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Key words:
- multiple myeloma /
- lipid metabolism /
- review
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表 1 脂质代谢相关药物在MM中可能的作用靶点及协同药物
分类 子分类 药物作用的靶点 协同药物 参考文献 FABP抑制剂 BMS309403 抑制MM细胞中的FABP5相关Myc-IRE/XBP1通路，驱动下调真核翻译起始因子5B，通过抑制未折叠蛋白反应诱导MM细胞内质网应激；抑制骨髓脂肪细胞提供的FABP4，削弱MM细胞摄取脂肪酸的能力，降低IL-6及RANKL等促炎因子的水平。 [5-6] 鱼油类 鱼油 抑制SREBP-1、STAT3通路，减少脂肪酸合成；激活PPARγ增加肝素前脂蛋白脂酶的活性，加快脂肪酸清除；选择性上调NRF2-ATF3/4-CHAC1通路降低谷胱甘肽水平，诱导MM细胞铁死亡。 硼替佐米 [7-9] 贝特类 非诺贝特 激活PPARα通路提高脂蛋白脂酶的活性，清除MM细胞中异常堆积的脂质。 伊沙佐米 [10-11] 他汀类 辛伐他汀 降低辅酶Q水平，致MM细胞氧化磷酸化受损。 硼替佐米 [12] 洛伐他汀 抑制甲羟戊酸途径减少异戊二烯供体的生成，破坏单克隆蛋白的运输诱导MM细胞死亡。 VSW1198 [13-14] 氟伐他汀 诱导t(4；14)阳性细胞香叶基香叶基焦磷酸耗竭激活了综合应激反应。 硼替佐米 [15] 匹伐他汀 在p53缺失的情况下，上调PUMA的活性，通过杂交结合前存活Bcl-2家族成员来促进BH3模拟杀伤并上调ATF4/ISR-NOXA通路。 维奈托克 [16-17] 微粒体甘油三酯转移蛋白抑制剂 洛美他派 靶向布鲁顿酪氨酸激酶调控CD38的下游信号转导，触发MM细胞中的细胞周期停滞和凋亡。 [18] 哺乳动物雷帕霉素靶蛋白抑制剂 替西罗莫司 抑制MM细胞中哺乳动物雷帕霉素靶蛋白通路激活，阻止MM细胞利用SR-BI从HDL-C中吸收胆固醇酯。 曲美替尼 [19-21] 依维莫司 通过IKZF3和Blimp-1介导Bcl-2上调。 维奈托克 [22] 抗LPAR2抗体 bs-10368R 抑制LPA-LPAR2轴及其下游MEK1/2-ERK1/2信号通路，抑制MM细胞线粒体氧化磷酸化产生ATP。 卡非佐米 [23] 鞘氨醇-1-磷酸受体调节剂 芬戈莫德 抑制S1P诱导的丝裂原活化蛋白激酶磷酸化。 卡非佐米 [24] 鞘氨醇激酶抑制剂 ABC294640 抑制S1P诱导的丝裂原活化蛋白激酶磷酸化；下调SET/PP2AC/PARK2途径诱导MM细胞系的线粒体自噬和凋亡。 卡非佐米 [24-25] SK1-I 抑制S1P诱导的丝裂原活化蛋白激酶磷酸化。 卡非佐米 [24] 葡萄糖神经酰胺合成酶抑制剂 依利格鲁司特 阻断神经酰胺转化为自噬相关鞘糖脂，上调TRAF3活性并抑制了破骨细胞的生成，改善MM骨病。 [26] ULK1抑制剂 MRT68921 阻断CD28-Ca2+-AMPK-ULK1/HuR/ATG5介导的脂滴自噬机制显著增加了脂滴数量，抑制了MM细胞的线粒体呼吸。 美法仑 [27] 
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