title: Cholesterol regulates VEGFR-1 (FLT-1) expression and signaling in acute leukemia cells.
abstract: VEGF receptors 1 (FLT-1) and 2 (KDR) are expressed on subsets of acute myeloid leukemia (AML) and acute lymphoid leukemia cells, in which they induce cell survival, proliferation, and migration. However, little is known about possible cofactors that regulate VEGF receptor expression and activation on leukemia cells. Here we show that cholesterol accumulates in leukemia-rich sites within bone marrow of xenotransplanted severe combined immunodeficient (SCID) mice. Therefore, we hypothesized that cholesterol-rich domains might regulate FLT-1 signaling and chemotaxis of acute leukemias. We then showed that FLT-1 accumulates in discrete cholesterol-rich membrane domains where it associates with caveolin-1 and that placenta growth factor (PlGF)/VEGF stimulation promotes FLT-1 localization in such cholesterol-rich domains. Accordingly, FLT-1 localization and its phosphorylation are abrogated by methyl-β-cyclodextrin (MβCD), which removes cellular cholesterol, and by nystatin, an inhibitor of lipid-raft endocytosis. Mechanistically, cholesterol increases FLT-1 expression and promotes PlGF/VEGF-induced leukemia cells viability and also induces VEGF production by the leukemia cells in vitro. Taken together, we conclude that cholesterol regulates VEGF:VEGFR-1 signaling on subsets of acute leukemias, modulating cell migration, and viability, which may be crucial for disease progression. Finally, we provide evidence obtained from human AML samples that primary leukemia cells accumulate significantly more cholesterol than do normal cells and that cholesterol accumulation correlates with disease aggressiveness.
authors.affiliation: Angiogenesis Group, Instituto Português de Oncologia Franscisco Gentil de Lisboa, EPE (CIPM/IPOLFG), Lisbon 1099-023, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Casalou
authors.forename: Ana
authors.initials: A
authors.lastname: Costa
authors.forename: Tânia
authors.initials: T
authors.lastname: Carvalho
authors.forename: Ana L
authors.initials: AL
authors.lastname: Gomes
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Zhu
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Sérgio
authors.initials: S
authors.lastname: Dias
mesh_terms: D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002784:Cholesterol / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D002784:Cholesterol; D040281:Vascular Endothelial Growth Factor Receptor-1