B-cell clonogenic activity of HIV-1 p17 variants is driven by PAR1-mediated EGF transactivation

Autor: Riccardo Dolcetti, Cinzia Giagulli, Francesca Caccuri, Alberto Zani, Pasqualina D'Ursi, Ekta Manocha, Arnaldo Caruso, Alessandro Orro, Simone Zorzan, Antonella Bugatti, Federica Filippini
Rok vydání: 2020
Předmět:
Cancer microenvironment
Transcriptional Activation
EXPRESSION
0301 basic medicine
Cell biology
Cancer Research
Lymphoma
Carcinogenesis
HIV Antigens
PHASE
TRASTUZUMAB
Drug development
HIV Infections
RAC1
Biology
Lymphocyte Activation
gag Gene Products
Human Immunodeficiency Virus
Article
ANGIOGENESIS
Phosphatidylinositol 3-Kinases
03 medical and health sciences
Transactivation
PROTEIN-COUPLED RECEPTORS
0302 clinical medicine
Growth factor receptor
medicine
Humans
Receptor
PAR-1
TRANSCRIPTION
ACTIVATED RECEPTORS
Clonogenic assay
Molecular Biology
PI3K/AKT/mTOR pathway
B cell
Cyclin-dependent kinase 1
ABL
Epidermal Growth Factor
CANCER
Oncogene Protein v-akt
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
HIV-1
GROWTH-FACTOR RECEPTOR
LYMPHANGIOGENESIS
Cancer research
Molecular Medicine
Signal Transduction
Zdroj: Cancer Gene Therapy
ISSN: 1476-5500
0929-1903
Popis: Combined antiretroviral therapy (cART) for HIV-1 dramatically slows disease progression among HIV+individuals. Currently, lymphoma represents the main cause of death among HIV-1-infected patients. Detection of p17 variants (vp17s) endowed with B-cell clonogenic activity in HIV-1-seropositive patients with lymphoma suggests their possible role in lymphomagenesis. Here, we demonstrate that the clonogenic activity of vp17s is mediated by their binding to PAR1 and to PAR1-mediated EGFR transactivation through Gq protein. The entire vp17s-triggered clonogenic process is MMPs dependent. Moreover, phosphoproteomic and bioinformatic analysis highlighted the crucial role of EGFR/PI3K/Akt pathway in modulating several molecules promoting cancer progression, including RAC1, ABL1, p53, CDK1, NPM, Rb, PTP-1B, and STAT1. Finally, we show that a peptide (F1) corresponding to the vp17s functional epitope is sufficient to trigger the PAR1/EGFR/PI3K/Akt pathway and bind PAR1. Our findings suggest novel potential therapeutic targets to counteract vp17-driven lymphomagenesis in HIV+patients.
Databáze: OpenAIRE
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