Article

Platelet-derived growth factor receptor alpha in glioma: a bad seed

University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Chinese journal of cancer 09/2011; 30(9):590-602. DOI: 10.5732/cjc.011.10236
Source: PubMed

ABSTRACT Recent collaborative, large-scale genomic profiling of the most common and aggressive brain tumor glioblastoma multiforme(GBM) has significantly advanced our understanding of this disease. The gene encoding platelet-derived growth factor receptor alpha(PDGFRα) was identified as the third of the top 11 amplified genes in clinical GBM specimens. The important roles of PDGFRα signaling during normal brain development also implicate the possible pathologic consequences of PDGFRα over-activation in glioma. Although the initial clinical trials using PDGFR kinase inhibitors have been predominantly disappointing, diagnostic and treatment modalities involving genomic profiling and personalized medicine are expected to improve the therapy targeting PDGFRα signaling. In this review, we discuss the roles of PDGFRαsignaling during development of the normal central nervous system(CNS) and in pathologic conditions such as malignant glioma. We further compare various animal models of PDGF-induced gliomagenesis and their potential as a novel platform of pre-clinical drug testing. We then summarize our recent publication and how these findings will likely impact treatments for gliomas driven by PDGFRα overexpression. A better understanding of PDGFRα signaling in glioma and their microenvironment, through the use of human or mouse models, is necessary to design a more effective therapeutic strategy against gliomas harboring the aberrant PDGFRα signaling.

0 Bookmarks
 · 
95 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of brain tumors in males is common but unexplained. While sex differences in disease are typically mediated through acute sex hormone actions, sex-specific differences in brain tumor rates are comparable at all ages, suggesting that factors other than sex hormones underlie this discrepancy. We found that mesenchymal glioblastoma (Mes-GBM) affects more males as the result of cell-intrinsic sexual dimorphism in astrocyte transformation. We used astrocytes from neurofibromin-deficient (Nf1-/-) mice expressing a dominant-negative form of the tumor suppressor p53 (DNp53) and treated them with EGF as a Mes-GBM model. Male Mes-GBM astrocytes exhibited greater growth and colony formation compared with female Mes-GBM astrocytes. Moreover, male Mes-GBM astrocytes underwent greater tumorigenesis in vivo, regardless of recipient mouse sex. Male Mes-GBM astrocytes exhibited greater inactivation of the tumor suppressor RB, higher proliferation rates, and greater induction of a clonogenic, stem-like cell population compared with female Mes-GBM astrocytes. Furthermore, complete inactivation of RB and p53 in Mes-GBM astrocytes resulted in equivalent male and female tumorigenic transformation, indicating that intrinsic differences in RB activation are responsible for the predominance of tumorigenic transformation in male astrocytes. Together, these results indicate that cell-intrinsic sex differences in RB regulation and stem-like cell function may underlie the predominance of GBM in males.
    Journal of Clinical Investigation 08/2014; DOI:10.1172/JCI71048 · 13.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Various types of cancer accounts for 10% of total death worldwide which necessitates better therapeutic strategies. Curcumin, a curcuminoid present in Curcuma longa, shown to exhibit antioxidant, anti-inflammatory and anticarcinogenic properties. Present study, we aimed to analyze inhibitory properties of curcumin towards virulent proteins for various cancers by computer aided virtual screening. Based on literature studies, twenty two receptors were selected which have critical virulent functions in various cancer. The binding efficiencies of curcumin towards selected targets were studied by molecular docking. Out of all, curcumin showed best results towards epidermal growth factor (EGF), virulent protein of gastric cancer; glutathione-S-transferase Pi gene (GST-PI), virulent protein for prostate cancer; platelet-derived growth factor alpha (PDGFA), virulent protein for mesothelioma and glioma compared with their natural ligands. The calculated binding energies of their docked conformations with curcumin found to be -7.59 kcal/mol, -7.98 kcal/mol and -7.93 kcal/mol respectively. Further, a comparative study was performed to screen binding efficiency of curcumin with two conventional antitumor agents, litreol and triterpene. Docking studies revealed that calculated binding energies of docked complex of litreol and EGF, GST-PI and PDGFA were found to be -5.08 kcal/mol, -3.69 kcal/mol and -1.86 kcal/mol respectively. The calculated binding energies of triterpene with EGF and PDGFA were found to be -4.02 kcal/mol and -3.11 kcal/mol respectively, whereas GST-PI showed +6.07 kcal/mol, indicate poor binding. The predicted pharmacological features of curcumin found to be better than litreol and triterpene. Our study concluded that curcumin has better interacting properties towards these cancer targets than their normal ligands and conventional antitumor agents. Our data pave insight for designing of curcumin as novel inhibitors against various types of cancer.
    Interdisciplinary Sciences Computational Life Sciences 03/2014; 6(1):13-24. DOI:10.1007/s12539-014-0170-8 · 0.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.
    The Journal of clinical investigation 07/2014; DOI:10.1172/JCI73093 · 15.39 Impact Factor

Full-text (4 Sources)

Download
15 Downloads
Available from
Jul 2, 2014