Spatial and temporal proteome dynamics of glioma cells during oncolytic adenovirus Delta-24-RGD infection
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Andrea González-Morales1,2,3, Aintzane Zabaleta2,4, Elizabeth Guruceaga2,5, Marta M. Alonso2,6,7, Marc García-Moure2,6,7, Joaquín Fernández-Irigoyen1,2,3,*, Enrique Santamaría1,2,3,*
1Clinical Neuroproteomics Group, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea, Pamplona, Spain
2IDISNA, Navarra Institute for Health Research, Pamplona, Spain
3Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Complejo Hospitalario de Navarra (CHN), Universidad Pública de Navarra (UPNA), Irunlarrea, Pamplona, Spain
4Oncohematology Area, University Hospital of Navarra, Center for Applied Medical Research, CIBERONC, Pamplona, Spain
5Bioinformatics Unit, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
6Program in Solid Tumors and Biomarkers, Foundation for the Applied Medical Research, Pamplona, Spain
7Department of Pediatrics, University Hospital of Navarra, Pamplona, Spain
*These authors share senior authorship
Enrique Santamaría, email: email@example.com
Keywords: adenovirus; Delta-24RGD infection; proteomics; glioma
Received: February 06, 2018 Accepted: June 22, 2018 Published: July 24, 2018
Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant glioma. Oncolytic adenoviruses are being modified to exploit the aberrant expression of proteins in tumor cells to increase the antiglioma efficacy. E1A mutant adenovirus Delta-24-RGD (DNX-2401) has shown a favorable toxicity profile and remarkable efficacy in a first-in-human phase I clinical trial. However, the comprehensive modulation of glioma metabolism in response to Delta-24-RGD infection is poorly understood. Integrating mass spectrometry based-quantitative proteomics, physical and functional interaction data, and biochemical approaches, we conducted a cell-wide study of cytosolic, nuclear, and secreted glioma proteomes throughout the early time course of Delta-24-RGD infection. In addition to the severe proteostasis impairment detected during the first hours post-infection (hpi), Delta-24-RGD induces a transient inhibition of signal transducer and activator of transcription 3 (STAT3), and transcription factor AP-1 (c-JUN) between 3 and 10hpi, increasing the nuclear factor kappa B (NF-κB) activity at 6hpi. Furthermore, Delta-24-RGD specifically modulates the activation dynamics of protein kinase C (PKC), extracellular signal–regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) pathways early in infection. At extracellular level, Delta-24-RGD triggers a time –dependent dynamic production of multitasking cytokines, and chemotactic factors, suggesting potential pleiotropic effects on the immune system reactivation. Taken together, these data help us to understand the mechanisms used by Delta-24-RGD to exploit glioma proteome organization. Further mining of this proteomic resource may enable design and engineering complementary adenoviral based-vectors to increase the specificity and potency against glioma.
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