DEAD-box RNA解旋酶DDX28通过改变生物能量学抑制MDA-MB-231细胞的细胞迁移和3D生长和侵袭。

IF 3.1 3区 生物学 Q3 CELL BIOLOGY
Molecular Biology of the Cell Pub Date : 2025-08-01 Epub Date: 2025-06-25 DOI:10.1091/mbc.E25-02-0052
Olivia Bebenek, Sydney A Pascetta, Joshua Steed, Morgan Mizzoni, Alexandria T Kellington, Margaret K Barnes, Tess Osorio-MacCready, James Uniacke
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引用次数: 0

摘要

缺氧是肿瘤微环境导致侵袭性表型的共同特征。对缺氧的主要反应是通过缺氧诱导因子(hfs)诱导基因程序。之前,我们发现DEAD-box RNA解旋酶DDX28通过与HIF-2α的相互作用负调控缺氧eif4e2导向的翻译。我们假设DDX28是一种抑制致癌HIF-2α轴的肿瘤抑制因子。在这里,我们在MDA-MB-231乳腺癌和U87MG胶质母细胞瘤细胞中过表达DDX28,与非癌性HEK293相比,它们分别具有非常低和正常的内源性DDX28水平。我们发现,DDX28抑制MDA-MB-231细胞的迁移、球形生长和侵袭,但不抑制U87MG细胞。然而,抑制不是通过HIF-2α基因程序,而是通过DDX28影响细胞生物能量学。DDX28水平改变了细胞利用线粒体呼吸和糖酵解生成ATP的方式。此外,这些过程的药理学抑制特异性地逆转了DDX28过表达的作用。该研究表明,低内源性DDX28水平促进了具有生物能量特征的细胞(如MDA-MB-231)在3D结构中的缺氧迁移和生长/侵袭。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The DEAD-box RNA helicase DDX28 suppresses cell migration and 3D growth and invasion in MDA-MB-231 cells by altering bioenergetics.

Hypoxia is a common characteristic of the tumor microenvironment leading to aggressive phenotypes. A major response to hypoxia is through the induction of gene programs by the hypoxia-inducible factors (HIF). Previously, we showed that the DEAD-box RNA helicase DDX28 negatively regulates hypoxic eIF4E2-directed translation through its interaction with HIF-2α. We hypothesized that DDX28 is a tumor suppressor that represses the oncogenic HIF-2α axis. Here, we overexpress DDX28 in MDA-MB-231 breast cancer and U87MG glioblastoma cells that have very low and normal endogenous levels of DDX28, respectively, compared with noncancerous HEK293. We show that DDX28 suppresses cell migration, spheroid growth, and invasion in MDA-MB-231, but not U87MG cells. However, suppression is not through the HIF-2α gene program, but through DDX28 impacting cellular bioenergetics. DDX28 levels altered how cells utilized mitochondrial respiration and glycolysis for ATP generation. Furthermore, the pharmacological inhibition of these processes specifically reversed the effects of DDX28 overexpression. This study shows that low endogenous DDX28 levels promote hypoxic migration, and growth/invasion in three-dimensional structures in cells that have a bioenergetic profile that favors glycolysis such as MDA-MB-231.

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来源期刊
Molecular Biology of the Cell
Molecular Biology of the Cell 生物-细胞生物学
CiteScore
6.00
自引率
6.10%
发文量
402
审稿时长
2 months
期刊介绍: MBoC publishes research articles that present conceptual advances of broad interest and significance within all areas of cell, molecular, and developmental biology. We welcome manuscripts that describe advances with applications across topics including but not limited to: cell growth and division; nuclear and cytoskeletal processes; membrane trafficking and autophagy; organelle biology; quantitative cell biology; physical cell biology and mechanobiology; cell signaling; stem cell biology and development; cancer biology; cellular immunology and microbial pathogenesis; cellular neurobiology; prokaryotic cell biology; and cell biology of disease.
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