KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis.
Lucas E CavallinQi MaJulian NaipauerSachin GuptaMani KurianPaola LocatelliPaolo RomanelliMehrdad NadjiPascal J Goldschmidt-ClermontEnrique A MesriPublished in: PLoS pathogens (2018)
Kaposi's sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth.
Keyphrases
- tyrosine kinase
- gene expression
- induced apoptosis
- high glucose
- signaling pathway
- diabetic rats
- cell cycle arrest
- endothelial cells
- sars cov
- epidermal growth factor receptor
- drug induced
- stem cells
- single cell
- cell death
- smooth muscle
- low grade
- antiretroviral therapy
- cell therapy
- endoplasmic reticulum stress
- machine learning
- deep learning
- bone marrow
- binding protein
- electronic health record
- vascular smooth muscle cells
- angiotensin ii
- single molecule