title: Vascular endothelial growth factor inhibits apoptotic death in hematopoietic cells after exposure to chemotherapeutic drugs by inducing MCL1 acting as an antiapoptotic factor.
abstract: We reported previously that vascular endothelial growth factor (VEGF) inhibits the apoptotic death of hematopoietic cells that is induced by exposure to ionizing radiation (O. Katoh et al., Cancer Res., 55: 5687-5692, 1995). In this study, we show that VEGF also inhibits apoptotic cell death that is induced by exposure to the chemotherapeutic drugs etoposide and doxorubicin. To elucidate the molecular mechanisms underlying this inhibitory effect of VEGF, we examined expression levels of BCL2 family proteins in CMK86, a human leukemia cell line, after treatment with VEGF. Northern blotting and immunoblotting analyses revealed that the expression level of MCL1, a member of the BCL2 family, was increased by VEGF. Moreover, to examine the effects of MCL1 on apoptotic cell death induced by exposure to etoposide, we generated a clonal U937 myeloid leukemia cell line transfected with vectors that promoted the constitutive expression of MCL1. MCL1 decreased the caspase 3 activity induced by exposure to etoposide and increased the viability of the transfected cells after etoposide exposure. Therefore, MCL1 may be involved in the inhibitory effect of VEGF on apoptotic cell death.
authors.affiliation: Department of Environment and Mutation, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan.
authors.forename: O
authors.initials: O
authors.lastname: Katoh
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Oguri
authors.forename: K
authors.initials: K
authors.lastname: Kuramoto
authors.forename: K
authors.initials: K
authors.lastname: Mihara
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Hirata
authors.forename: H
authors.initials: H
authors.lastname: Watanabe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins / Q000096:biosynthesis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology; D008222:Lymphokines / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C494819:BAD protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D005047:Etoposide; D004317:Doxorubicin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases