A cell-autonomous positive-signaling circuit associated with the PDGF-NO-ID4-regulatory axis in glioblastoma cells.
Most cancer-related signaling pathways sustain their active or inactive status via genetic mutations or various regulatory mechanisms. Previously, we demonstrated that platelet-derived growth factor (PDGF) activates Notch signaling through nitric oxide (NO)-signaling-driven activation of inhibitor of differentiation 4 (ID4) in glioblastoma (GBM) stem cells (GSCs) and endothelial cells in the vascular niche of GBM, leading to maintenance of GSC traits and GBM progression. Here, we determined that the PDGF-NO-ID4-signaling axis is constantly activated through a positive regulatory circuit. ID4 expression significantly increased PDGF subunit B expression in both in vitro cultures and in vivo tumor xenografts and regulated NO synthase 2 (NOS2) expression and NO production by activating PDGF signaling, as well as that of its receptor (PDGFR). Additionally, ectopic expression of PDGFRα, NOS2, or ID4 activated the PDGF-NO-ID4-signaling circuit and enhanced the self-renewal of GBM cell lines. These results suggested that the positive regulatory circuit associated with PDGF-NO-ID4 signaling plays a pivotal role in regulating the self-renewal and tumor-initiating capacity of GSCs and might provide a promising therapeutic target for GBM.
Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Kiyoung
K
Eun
Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Hye-Min
HM
Jeon
Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
Sung-Ok
SO
Kim
Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Sang-Hun
SH
Choi
Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Seon Yong
SY
Lee
Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Xiong
X
Jin
Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea. Electronic address: biokim@hallym.ac.kr.
Sung-Chan
SC
Kim
Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea. Electronic address: hg-kim@korea.ac.kr.
Hyunggee
H
Kim
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics* / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D020574:Proto-Oncogene Proteins c-sis; D009569:Nitric Oxide; D008156:Luciferases; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D020796:Receptor, Platelet-Derived Growth Factor alpha
Cell-signaling circuit; Glioblastoma cells; Inhibitor of differentiation 4; Nitric oxide; Platelet-derived growth factor