PTEN regulates PDGF ligand switch for β-PDGFR signaling in prostate cancer.
Platelet-derived growth factor (PDGF) family members are potent growth factors that regulate cell proliferation, migration, and transformation. Clinical studies have shown that both PDGF receptor β (β-PDGFR) and its ligand PDGF D are up-regulated in primary prostate cancers and bone metastases, whereas PDGF B, a classic ligand for β-PDGFR, is not frequently detected in clinical samples. In this study, we examined the role of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in the regulation of PDGF expression levels using both a prostate-specific, conditional PTEN-knockout mouse model and mouse prostate epithelial cell lines established from these mice. We found an increase in PDGF D and β-PDGFR expression levels in PTEN-null tumor cells, accompanied by a decrease in PDGF B expression. Among Akt isoforms, increased Akt3 expression was most prominent in mouse PTEN-null cells, and phosphatidylinositol 3-kinase/Akt activity was essential for the maintenance of increased PDGF D and β-PDGFR expression. In vitro deletion of PTEN resulted in a PDGF ligand switch from PDGF B to PDGF D in normal mouse prostate epithelial cells, further demonstrating that PTEN regulates this ligand switch. Similar associations between PTEN status and PDGF isoforms were noted in human prostate cancer cell lines. Taken together, these results suggest a mechanism by which loss of PTEN may promote prostate cancer progression via PDGF D/β-PDGFR signal transduction.
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan.
M Katie
MK
Conley-LaComb
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan.
Wei
W
Huang
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Shihua
S
Wang
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan.
Dongping
D
Shi
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan.
Young Suk
YS
Jung
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan.
Abdo
A
Najy
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan.
Rafael
R
Fridman
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan; Department of Urology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan.
R Daniel
RD
Bonfil
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan; Department of Urology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan.
Michael L
ML
Cher
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Electronic address: yqchen@wfubmc.edu.
Yong Q
YQ
Chen
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan. Electronic address: hrckim@med.wayne.edu.
Hyeong-Reh Choi
HC
Kim
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D008024:Ligands; D010982:Platelet-Derived Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse