title: Kaposi sarcoma associated herpesvirus (KSHV) induces AKT hyperphosphorylation, bortezomib-resistance and GLUT-1 plasma membrane exposure in THP-1 monocytic cell line.
abstract: BACKGROUND
  Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway regulates multiple cellular processes such as cell proliferation, evasion from apoptosis, migration, glucose metabolism, protein synthesis and proper differentiation in immune cells. Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus associated with several human malignancies, expresses a variety of latent and lytic proteins able to activate PI3K/AKT pathway, promoting the growth of infected cells and a successful viral infection.
  
  
  RESULTS
  We found that KSHV latent infection of THP-1 cells, a human monocytic cell line derived from an acute monocytic leukemia patient, resulted in an increase of AKT phoshorylation, not susceptible to bortezomib-induced dephosphorylation, compared to the mock-infected THP-1. Accordingly, THP-1-infected cells displayed increased resistance to the bortezomib cytotoxic effect in comparison to the uninfected cells, which was counteracted by pre-treatment with AKT-specific inhibitors. Finally, AKT hyperactivation by KSHV infection correlated with plasma membrane exposure of glucose transporter GLUT1, particularly evident during bortezomib treatment. GLUT1 membrane trafficking is a characteristic of malignant cells and underlies a change of glucose metabolism that ensures the survival to highly proliferating cells and render these cells highly dependent on glycolysis. GLUT1 membrane trafficking in KSHV-infected THP-1 cells indeed led to increased sensitivity to cell death induced by the glycolysis inhibitor 2-Deoxy-D-glucose (2DG), further potentiated by its combination with bortezomib.
  
  
  CONCLUSIONS
  KSHV confers to the THP-1 infected cells an oncogenic potential by altering the phosphorylation, expression and localization of key molecules that control cell survival and metabolism such as AKT and GLUT1. Such modifications in one hand lead to resistance to cell death induced by some chemotherapeutic drugs such as bortezomib, but on the other hand, offer an Achilles heel, rendering the infected cells more sensitive to other treatments such as AKT or glycolysis inhibitors. These therapeutic strategies can be exploited in the anticancer therapy of KSHV-associated malignancies.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gonnella
authors.forename: Roberta
authors.initials: R
authors.lastname: Santarelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Farina
authors.forename: Marisa
authors.initials: M
authors.lastname: Granato
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Orazi
authors.forename: Alberto
authors.initials: A
authors.lastname: Faggioni
authors.forename: Mara
authors.initials: M
authors.lastname: Cirone
mesh_terms: D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011719:Pyrazines / Q000494:pharmacology*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015398:Signal Transduction
chemical_list: D001897:Boronic Acids; D051272:Glucose Transporter Type 1; D011719:Pyrazines; C495677:SLC2A1 protein, human; D000069286:Bortezomib; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt