title: Increased expression of platelet-derived growth factor associated protein-1 is associated with PDGF-B mediated glioma progression.
abstract: The current treatment therapies available for malignant gliomas are inadequate. There is an urgent need to develop more effective therapies by characterizing the molecular pathogenesis of the disease. Over expression of platelet-derived growth factor (PDGF) ligands and receptors have been reported in malignant gliomas. Platelet-derived growth factor associated protein-1 (PDAP-1) is reported to modulate the mitogenic activity of PDGF ligands, but to date, there is no information concerning its role in PDGF-mediated glioma cell proliferation. This study aimed to characterize the role of PDAP-1 in PDGF-mediated glioma proliferation. The expression of PDAP-1 was observed to be significantly increased (p<0.05) in grade IV glioma tissue and cell lines compared to grade III. siRNA-mediated knockdown of PDAP-1 reduced the expression of PDGF-B and its downstream genes (Akt1/Protein kinase B (PKB) and phosphoinositide-dependent kinase-1 (PDK1) by up to 50%. In PDAP-1 knockdown glioma cells, more than a twofold reduction was also observed in the level of phosphorylated Akt. Interestingly, knockdown of PDAP-1 in combination with PDGF-B antibody inhibited glioma cell proliferation through activation of Caspase 3/7 and 9. We also demonstrate that PDAP-1 co-localizes with PDGF-B in the cytoplasm of glioma cells, and an interaction between both of the proteins was established. Collectively, these findings suggest that the expression of PDAP-1 is associated with disease malignancy, and its inhibition reduced the proliferation of malignant glioma cells through down-regulation of PDGF-B/Akt/PDK1 signaling. Thus, this study establishes PDAP-1 as an effecter of PDGF signaling in glioma cells and suggests that it could also be a promising therapeutic target.
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Sharma
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Anand
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Sandeep Kumar
authors.initials: SK
authors.lastname: Srivastava
authors.affiliation: Proteomics and Structural Biology Unit, Institute of genomics and Integrative Biology, New Delhi 110025, India.
authors.forename: Vignesh
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai, India.
authors.forename: Nilesh Laxman
authors.initials: NL
authors.lastname: Gardi
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Aasma
authors.initials: A
authors.lastname: Nalwa
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Dinda
authors.affiliation: Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Parthaprasad
authors.initials: P
authors.lastname: Chattopadhyay
authors.affiliation: Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: savita11@gmail.com.
authors.forename: Savita
authors.initials: S
authors.lastname: Yadav
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D053078:Membrane Potential, Mitochondrial; D060787:Neoplasm Grading; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C103312:PDAP1 protein, human; D020574:Proto-Oncogene Proteins c-sis; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053179:Caspase 7
keywords: Apoptosis; Glioma; Interaction; PDAP-1; PDGF; Signaling