title: VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition.
abstract: Similar to endothelial cells (ECs), vascular endothelial growth factor (VEGF) induces Bcl-2 expression on VEGF receptor-positive (VEGFR(+)) primary leukemias and cell lines, promoting survival. We investigated the molecular pathways activated by VEGF on such leukemias, by performing a gene expression analysis of VEGF-treated and untreated HL-60 leukemic cells. One gene to increase after VEGF stimulation was heat shock protein 90 (Hsp90). This was subsequently confirmed at the protein level, on primary leukemias and leukemic cell lines. VEGF increased the expression of Hsp90 by interacting with KDR and activating the mitogen-activated protein kinase cascade. In turn, Hsp90 modulated Bcl-2 expression, as shown by a complete blockage of VEGF-induced Bcl-2 expression and binding to Hsp90 by the Hsp90-specific inhibitor geldanamycin (GA). GA also blocked the VEGF-induced Hsp90 binding to APAF-1 on leukemic cells, a mechanism shown to inhibit apoptosis. Notably, VEGF blocked the proapoptotic effects of GA, correlating with its effects at the molecular level. Earlier, we showed that in some leukemias, a VEGF/KDR autocrine loop is essential for cell survival, whereas here we identified the molecular correlates for such an effect. We also demonstrate that the generation of a VEGF/VEGFR autocrine loop on VEGFR(+) cells such as ECs, also protected them from apoptosis. Infection of ECs with adenovirus-expressing VEGF resulted in elevated Hsp90 levels, increased Bcl-2 expression, and resistance to serum-free or GA-induced apoptosis. In summary, we demonstrate that Hsp90 mediates antiapoptotic and survival-promoting effects of VEGF, which may contribute to the survival advantage of VEGFR(+) cells such as subsets of leukemias.
authors.affiliation: Division of Hematology/Oncology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Dias
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Shmelkov
authors.forename: George
authors.initials: G
authors.lastname: Lam
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones; D002470:Cell Survival / Q000187:drug effects*; D016895:Culture Media, Serum-Free; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects*; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D047029:Lactams, Macrocyclic; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D008222:Lymphokines / Q000494:pharmacology*; D020033:Protein Isoforms / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000502:physiology; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000911:Antibodies, Monoclonal; D016227:Benzoquinones; D016895:Culture Media, Serum-Free; D016228:Endothelial Growth Factors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008222:Lymphokines; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D011809:Quinones; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; C001277:geldanamycin