PKCδ maintains phenotypes of tumor initiating cells through cytokine-mediated autocrine loop with positive feedback.
The existence of tumor initiating cells (TICs) has been emerged as a good therapeutic target for treatment of glioblastoma that is the most aggressive brain tumor with poor prognosis. However, the molecular mechanisms that regulate the phenotypes of TICs still remain obscure. In this study, we found that PKCδ, among PKC isoforms, is preferentially activated in TICs and acts as a critical regulator for the maintenance of TICs in glioblastoma. By modulating the expression levels or activity of PKCδ, we demonstrated that PKCδ promotes self-renewal and tumorigenic potentials of TICs. Importantly, we found that the activation of PKCδ persists in TICs through an autocrine loop with positive feedback that was driven by PKCδ/STAT3/IL-23/JAK signaling axis. Moreover, for phenotypes of TICs, we showed that PKCδ activates AKT signaling component by phosphorylation specifically on Ser473. Taken together, we proposed that TICs regulate their own population in glioblastoma through an autocrine loop with positive feedback that is driven by PKCδ-dependent secretion of cytokines.
Department of Life Science, Laboratory of Molecular Biochemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
R-K
RK
Kim
Department of Life Science, Laboratory of Molecular Biochemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
Y
Y
Suh
Department of Life Science, Laboratory of Molecular Biochemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
E
E
Hwang
Department of Life Science, Laboratory of Molecular Biochemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
K-C
KC
Yoo
Molecular and Cellular Imaging Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
K-S
KS
Choi
Functional Genoproteome Research Centre, Konkuk University, Seoul, Korea.
S
S
An
Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
S-G
SG
Hwang
Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, Korea.
I-G
IG
Kim
Department of Life Science, Laboratory of Molecular Biochemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.|Laboratory of Radiation Exposure and Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
M-J
MJ
Kim
Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
H-J
HJ
Lee
Department of Life Science, Laboratory of Molecular Biochemistry, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
S-J
SJ
Lee
D000818:Animals; D019898:Autocrine Communication; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta