文章：

线粒体肽人类素促进胶质母细胞瘤细胞的化疗耐药性

Mitochondrial Peptide Humanin Facilitates Chemoresistance in Glioblastoma Cells

原文发布日期：11 August 2023

DOI: 10.3390/cancers15164061

类型: Article

开放获取: 是

英文摘要：

Humanin (HN) is a mitochondrial-derived peptide with robust cytoprotective effects in many cell types. Although the administration of HN analogs has been proposed to treat degenerative diseases, its role in the pathogenesis of cancer is poorly understood. Here, we evaluated whether HN affects the chemosensitivity of glioblastoma (GBM) cells. We found that chemotherapy upregulated HN expression in GBM cell lines and primary cultures derived from GBM biopsies. An HN analog (HNGF6A) boosted chemoresistance, increased the migration of GBM cells and improved their capacity to induce endothelial cell migration and proliferation. Chemotherapy also upregulated FPR2 expression, an HN membrane-bound receptor, and the HNGF6A cytoprotective effects were inhibited by an FPR2 receptor antagonist (WRW4). These effects were observed in glioma cells with heterogeneous genetic backgrounds, i.e., glioma cells with wild-type (wtIDH) and mutated (mIDH) isocitrate dehydrogenase. HN silencing using a baculoviral vector that encodes for a specific shRNA for HN (BV.shHN) reduced chemoresistance, and impaired the migration and proangiogenic capacity of GBM cells. Taken together, our findings suggest that HN boosts the hallmark characteristics of GBM, i.e., chemoresistance, migration and endothelial cell proliferation. Thus, strategies that inhibit the HN/FPR2 pathway may improve the response of GBM to standard therapy

摘要翻译： 

Humanin（HN）是一种线粒体衍生肽，对多种细胞类型具有显著的细胞保护作用。尽管已有研究提出使用HN类似物治疗退行性疾病，但其在癌症发病机制中的作用尚不明确。本研究评估了HN是否影响胶质母细胞瘤（GBM）细胞的化疗敏感性。我们发现化疗能上调GBM细胞系及源自GBM活检原代培养物中HN的表达。一种HN类似物（HNGF6A）可增强化疗抵抗性、促进GBM细胞迁移，并提升其诱导内皮细胞迁移与增殖的能力。化疗同时上调了HN的膜结合受体FPR2的表达，而FPR2受体拮抗剂（WRW4）能够抑制HNGF6A的细胞保护作用。这些效应在具有异质遗传背景的胶质瘤细胞中均被观察到，即同时存在于野生型IDH（wtIDH）与突变型IDH（mIDH）的异柠檬酸脱氢酶胶质瘤细胞中。通过编码特异性HN shRNA的杆状病毒载体（BV.shHN）沉默HN表达后，GBM细胞的化疗抵抗性降低，迁移能力及促血管生成能力受损。综上所述，我们的研究结果表明HN能够增强GBM的典型特征，包括化疗抵抗性、迁移能力和内皮细胞增殖能力。因此，抑制HN/FPR2通路的策略可能改善GBM对标准治疗的反应。

原文链接：

Mitochondrial Peptide Humanin Facilitates Chemoresistance in Glioblastoma Cells