Sulforaphane inhibits multiple myeloma cell-induced osteoclast differentiation and macrophage proliferation by elevating ferroportin1.

IF 2.7 4区 医学 Q3 ONCOLOGY
Weichu Sun, Jingqi Sun, Wei Hu, Cong Luo, Zhongwei Lu, Fen He, Hongyan Zhao, Xi Zeng, Deliang Cao, Junjun Li, Chang Zhang, Jiliang Xia
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引用次数: 0

Abstract

Purpose: Osteolysis is a common complication in patients with multiple myeloma (MM). Our previous studies have demonstrated that MM cells can promote osteoclast differentiation of macrophages. In this study, we explored the effect of sulforaphane (SFN), a natural NRF2 activator found in broccoli, on MM cell-induced osteoclast differentiation.

Methods: Conditional medium (CM) derived from MM cells was used to induce osteoclast differentiation, and TRAP staining was performed to examine osteoclast. Gene expression was detected by western blotting or real-time PCR. Cell counting and EdU staining were performed to test macrophage proliferation.

Results: We showed that the CM of MM cells downregulated the expression of ferroportin1 (Fpn1), the only known iron exporter in vertebrate cells, thereby increasing cellular iron levels in murine macrophage cells RAW264.7. Deferoxamine (DFO), an iron chelator, effectively blocked MM cell CM-induced osteoclast differentiation and macrophage proliferation, suggesting that iron overload played a key role in these cellular events. Subsequent mechanistic investigations revealed that MM cell CM induced osteoclast differentiation and macrophage proliferation by activating the JNK/AP-1/NFATC1 pathway and PI3K/AKT pathway. SFN was found to increase Fpn1 expression, leading to decreased cellular iron levels in RAW264.7 cells activated by MM cell CM. Importantly, the osteoclast differentiation and macrophage proliferation induced by MM cell CM were significantly inhibited by SFN.

Conclusion: Altogether, our findings indicated that SFN inhibits MM cell-induced osteoclast differentiation and macrophage proliferation by elevating FPN1 levels. SFN could be a promising therapeutic strategy for MM-associated osteolysis.

萝卜硫素通过提高铁转运蛋白1抑制多发性骨髓瘤细胞诱导的破骨细胞分化和巨噬细胞增殖。
目的:骨溶解是多发性骨髓瘤(MM)的常见并发症。我们之前的研究表明MM细胞可以促进巨噬细胞的破骨细胞分化。在这项研究中,我们探索了萝卜硫素(SFN)对MM细胞诱导的破骨细胞分化的影响,这是西兰花中发现的一种天然NRF2激活剂。方法:采用MM细胞条件培养基(CM)诱导破骨细胞分化,并用TRAP染色检测破骨细胞。采用western blotting或real-time PCR检测基因表达。细胞计数和EdU染色检测巨噬细胞增殖。结果:我们发现MM细胞的CM下调了铁转运蛋白1 (Fpn1)的表达,这是脊椎动物细胞中唯一已知的铁输出蛋白,从而增加了小鼠巨噬细胞RAW264.7中的细胞铁水平。铁螯合剂去铁胺(DFO)可有效阻断MM细胞cm诱导的破骨细胞分化和巨噬细胞增殖,表明铁超载在这些细胞事件中起关键作用。随后的机制研究发现MM细胞CM通过激活JNK/AP-1/NFATC1通路和PI3K/AKT通路诱导破骨细胞分化和巨噬细胞增殖。发现SFN增加Fpn1的表达,导致MM细胞CM激活的RAW264.7细胞中细胞铁水平降低。重要的是,SFN显著抑制MM细胞CM诱导的破骨细胞分化和巨噬细胞增殖。结论:总之,我们的研究结果表明,SFN通过提高FPN1水平抑制MM细胞诱导的破骨细胞分化和巨噬细胞增殖。SFN可能是mm相关性骨溶解的一种有前景的治疗策略。
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来源期刊
CiteScore
6.10
自引率
3.30%
发文量
116
审稿时长
2.5 months
期刊介绍: Addressing a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels, Cancer Chemotherapy and Pharmacology is an eminent journal in the field. The primary focus in this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase I, II and III trials. It is essential reading for pharmacologists and oncologists giving results recorded in the following areas: clinical toxicology, pharmacokinetics, pharmacodynamics, drug interactions, and indications for chemotherapy in cancer treatment strategy.
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