PO.MCB09.04 · 分子与细胞生物学
精胺以不依赖翻译的方式增强胶质母细胞瘤中的氧化磷酸化
Spermine enhances oxidative phosphorylation independently of translation in glioblastoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胶质母细胞瘤（GBM）是最具侵袭性和致死性的原发性恶性脑肿瘤，平均生存期仅为15个月，凸显了对新型治疗策略的需求。多胺是细胞增殖所必需的带正电小分子，在包括GBM在内的多种癌症类型中经常失调。尽管如此，其在肿瘤发生中的独特作用尚未得到很好的表征。存在三种主要多胺：腐胺、亚精胺和精胺。腐胺转化为亚精胺，后者进一步转化为精胺。亚精胺的作用已被充分定义，因为它作为eIF5a-脱氧羟腐胺的前体，后者经过羟腐胺化以促进生长因子的翻译。精胺合成酶（SMS）是催化亚精胺转化为精胺的酶，在高级别胶质瘤中上调。初步数据提示SMS对GBM肿瘤的发展和生长是必需的，支持多胺代谢可作为GBM可靶向脆弱性的观点。然而，精胺（SMS的产物）在GBM中的具体作用仍然未知。我们假设精胺在GBM中具有独特的、非冗余的细胞功能，并旨在使用CRISPR介导的自体GBM小鼠模型阐明其作用。在该模型中，通过子宫内电穿孔（IUE）将编码Cas9和靶向抑癌基因PTEN、P53和NF1以及相关多胺基因的引导RNA的质粒导入小鼠胚胎，从而导致GBM肿瘤的发展。利用该系统，我们发现SMS敲除（KO）在体外和体内均显著抑制GBM生长。有趣的是，补充生理浓度的精胺未能恢复SMS KO细胞的细胞活力和氧化磷酸化（OCR），而野生型细胞在补充精胺后表现出OCR的强劲增加。进一步研究揭示精胺以不依赖翻译的方式增强OCR，提示其可能通过翻译后修饰（PTM）机制发挥作用。正在进行的研究旨在进一步表征SMS和精胺在GBM代谢和肿瘤生长中的作用。这些发现提示精胺是GBM发展和进展的关键调控因子，并可能为治疗干预提供一个新的代谢靶点。
查看英文原文 English abstract
Glioblastoma (GBM) is the most aggressive and lethal primary malignant brain tumor, with a mean survival of only 15 months, emphasizing the need for novel therapeutic strategies. Polyamines, small positively charged molecules necessary for cell proliferation, are frequently dysregulated in multiple cancer types, including GBM. Despite this, their distinct role in tumorigenesis has not been well characterized. There are three major polyamines: putrescine, spermidine, and spermine. Putrescine is converted into spermidine, which is further converted into spermine. The role of spermidine has been well defined, as it serves as a precursor for eIF5a-deoxyhypusine, which undergoes hypusination to promote translation of growth factors. Spermine Synthase (SMS), the enzyme that catalyzes the conversion of spermidine to spermine, is upregulated in high-grade gliomas. Preliminary data suggests that SMS is necessary for GBM tumor development and growth, supporting the idea that polyamine metabolism can be a targetable vulnerability in GBM. However, the specific role of spermine, the product of SMS, in GBM remains unknown. We hypothesize that spermine has distinct, non-redundant cellular functions in GBM and aim to elucidate its role using a CRISPR-mediated autochthonous mouse model of GBM. In this model, a plasmid encoding Cas9 and guide RNAs targeting the tumor suppressors PTEN, P53, and NF1 along with polyamine-related genes of interest are introduced into mouse embryos via intrauterine electroporation (IUE), leading to GBM tumor development. Utilizing this system, we have found that SMS knockout (KO) significantly inhibits GBM growth in vitro and in vivo . Interestingly, supplementing physiological concentrations of spermine failed to restore cell viability and oxidative phosphorylation (OCR) in SMS KO cells, while wild-type cells exhibited a robust increase in OCR upon spermine supplementation. Further investigation revealed spermine enhances OCR independently of translation, suggesting that it may function through a post-translational modification (PTM) mechanism. Ongoing studies aim to further characterize the role of SMS and spermine in GBM metabolism and tumor growth. These findings suggest that spermine is a critical regulator of GBM development and progression and may offer a novel metabolic target for therapeutic intervention.
利益披露 Disclosure
A. Carbone, None..
T. Horton, None..
A. Rana, None..
S. Welford, None.