微鬼臼毒素通过抑制表面受体IFG1R和ALK改变神经母细胞瘤的EMT

IF 1.6 4区医学 Q4 CELL BIOLOGY

Growth Hormone & Igf Research Pub Date : 2025-02-20 DOI:10.1016/j.ghir.2025.101638

Poonam Bhagriya , Afridi Shaikh , Hetal Roy

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引用次数: 0

摘要

神经母细胞瘤（NB）是一种起源于胚胎交感肾上腺细胞的儿科癌症。尽管它起源于儿科，但由于缺乏特异性的治疗方法，NB主要像成人一样采用非小细胞肺癌的治疗策略。为了改善神经母细胞瘤患者的治疗效果，开发专门针对神经母细胞瘤基因突变或分子通路的药物是必要的。胰岛素样生长因子1受体（IGF1R）的过度表达与多种恶性肿瘤有关，包括儿科癌症。我们假设通过植物化学化合物抑制IGF1R与ALK （NB特异性突变）可以有效地治疗NB，同时避免不良的细胞毒性作用。我们评估了Picropodophyllotoxin （PPP）作为IGF1R抑制剂治疗NB的疗效。24 h后，PPP对SH-SY5Y、NB细胞的IC50值为0.501 μM。分子对接研究表明，PPP与IGF1R的结合评分为−7.5 kcal/mol，与ALK的结合评分为−8.8 kcal/mol。这表明PPP不仅结合并抑制IGF1R，而且对ALK也有很强的亲和力。通过基因表达研究、密度分析、划痕试验和AO/EtBr差异染色来评估PPP对NB细胞的作用。转录物表达和密度分析显示，PPP可下调NB细胞中的IGF1R和ALK。间充质标志物SNAIL的下调和上皮标志物E-cadherin的上调表明NB细胞从间充质向上皮转变，表明PPP处理抑制了NB细胞的迁移和增殖。在我们的研究中，划痕试验结果进一步支持了这一点。此外，p53、BAX和BCL2基因表达分析表明，PPP诱导NB细胞凋亡。AO/EtBr鉴别染色显示PPP作用24 h后NB细胞出现凋亡现象。虽然还需要进一步的研究来探索使用PPP来抑制IGF1R和ALK的受体靶向方法。

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Picropodophyllotoxin alters EMT in neuroblastoma via inhibition of surface receptors IFG1R and ALK

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Picropodophyllotoxin alters EMT in neuroblastoma via inhibition of surface receptors IFG1R and ALK

Neuroblastoma (NB) is a type of paediatric cancer that originates from embryonic sympathoadrenal cells. Despite its paediatric origin, NB is mostly treated with strategy of non-small cell lung cancer like adults due to lack of specific therapeutic approach. To improve treatment outcome for NB patients, developing drugs that specifically target the genetic mutations or molecular pathways involved in neuroblastoma is necessary. Overexpression of the insulin-like growth factor 1 receptor (IGF1R) has been linked to various malignancies, including paediatric cancers. We hypothesized that inhibiting IGF1R with ALK (NB specific mutation) by phytochemical compound could effectively treat NB while avoiding undesirable cytotoxic effects. We evaluated the efficacy of Picropodophyllotoxin (PPP) as IGF1R inhibitor, for treatment of NB. The IC₅₀ value of PPP on SH-SY5Y, NB cells after 24 h of treatment was found to be 0.501 μM. Molecular docking studies revealed that PPP had a binding score of −7.5 kcal/mol with IGF1R and − 8.8 kcal/mol with ALK. This suggests that PPP not only binds to and inhibits IGF1R but also has a strong affinity for ALK. Gene expression studies, densitometric analysis, scratch assays, and AO/EtBr differential staining were used to evaluate the efficacy of PPP in NB cells. Transcript expression and densitometric analysis revealed that PPP could downregulate IGF1R and ALK in NB cells. Downregulation of SNAIL, a mesenchymal marker, and upregulation of E-cadherin, an epithelial marker, indicated a mesenchymal to epithelial transition in NB cells, suggesting that PPP treatment inhibited NB cell migration and proliferation. This was further supported by scratch assay results in our study. Furthermore, gene expression analysis of p53, BAX and BCL2 indicated that PPP induces apoptosis in NB cells. AO/EtBr differential staining revealed apoptotic phenomena in NB cells after 24 h of PPP treatment. Although further research is needed to explore the receptor targeting approach using PPP for IGF1R and ALK inhibition.

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来源期刊

Growth Hormone & Igf Research 医学-内分泌学与代谢

CiteScore

3.30

自引率

0.00%

发文量

审稿时长

57 days

期刊介绍： Growth Hormone & IGF Research is a forum for research on the regulation of growth and metabolism in humans, animals, tissues and cells. It publishes articles on all aspects of growth-promoting and growth-inhibiting hormones and factors, with particular emphasis on insulin-like growth factors (IGFs) and growth hormone. This reflects the increasing importance of growth hormone and IGFs in clinical medicine and in the treatment of diseases.