Han, Suji Shin, Hyemi Lee, Jin-Ku Liu, Zhaoqi Rabadan, Raul Lee, Jeongwu Shin, Jihye Lee, Cheolju Yang, Heekyoung Kim, Donggeon Kim, Sung Heon Kim, Jooyeon Oh, Jeong-Woo Kong, Doo-Sik Lee, Jung-Il Seol, Ho Jun Choi, Jung Won Kang, Hyun Ju Nam, Do-Hyun 2024-01-19T18:33:49Z 2024-01-19T18:33:49Z 2021-09-05 2019-12 1226-3613 https://pubs.kist.re.kr/handle/201004/119274 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. English 생화학분자생물학회 Secretome analysis of patient-derived GBM tumor spheres identifies midkine as a potent therapeutic target Article 10.1038/s12276-019-0351-y 1 Experimental & Molecular Medicine, v.51 Experimental & Molecular Medicine 51 N scie scopus kci 000502858700001 2-s2.0-85076164071 Biochemistry & Molecular Biology Medicine, Research & Experimental Biochemistry & Molecular Biology Research & Experimental Medicine Article CHECKPOINT KINASE INHIBITOR CANCER STEM-CELLS DNA-DAMAGE IN-VITRO GROWTH ROLES EXPRESSION APOPTOSIS P53