Secretome analysis of patient-derived GBM tumor spheres identifies midkine as a potent therapeutic target

Title
Secretome analysis of patient-derived GBM tumor spheres identifies midkine as a potent therapeutic target
Authors
이철주신지혜한수지신혜미이진구Zhaoqi LiuRaul Rabadan이정우양희경김동건김성헌김주연오정우공두식이정일설호준최정원강현주남도현
Issue Date
2019-12
Publisher
Experimental & molecular medicine
Citation
VOL 51, NO 12, 147
Abstract
Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of gliomainitiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis.
URI
http://pubs.kist.re.kr/handle/201004/72035
ISSN
1226-3613
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KIST Publication > Article
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