title: Pigment epithelium-derived factor (PEDF) inhibits survival and proliferation of VEGF-exposed multiple myeloma cells through its anti-oxidative properties.
abstract: Vascular endothelial growth factor (VEGF) has been reported not only to induce angiogenesis within the bone marrow, but also directly stimulate the proliferation and survival of multiple myeloma cells, thus being involved in the development and progression of this second most common hematological malignancy. We, along with others, have found that pigment epithelium-derived factor (PEDF) has anti-angiogenic and anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of VEGF. However, effects of PEDF on VEGF-exposed myeloma cells remain unknown. In this study, we examined whether and how PEDF could inhibit the VEGF-induced proliferation and survival of myeloma cells. PEDF, a glutathione peroxidase mimetic, ebselen, or an inhibitor of NADPH oxidase, diphenylene iodonium significantly inhibited the VEGF-induced reactive oxygen species (ROS) generation, increase in anti-apoptotic and growth-promoting factor, myeloid cell leukemia 1 (Mcl-1) expression, and proliferation in U266 myeloma cells. VEGF blocked apoptosis of multiple myeloma cells isolated from patients, which was prevented by PEDF. PEDF also reduced p22phox levels in VEGF-exposed U266 cells. Furthermore, overexpression of dominant-negative human Rac-1 mutant mimicked the effects of PEDF on ROS generation and Mcl-1 expression in U266 cells. Our present study suggests that PEDF could block the VEGF-induced proliferation and survival of multiple myeloma U266 cells through its anti-oxidative properties via suppression of p22phox, one of the membrane components of NADPH oxidase. Suppression of VEGF signaling by PEDF may be a novel therapeutic target for multiple myeloma.
authors: Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, Japan.
authors: Ritsuko
authors: R
authors: Seki
authors: Sho-ichi
authors: S
authors: Yamagishi
authors: Takanori
authors: T
authors: Matsui
authors: Takafumi
authors: T
authors: Yoshida
authors: Takuji
authors: T
authors: Torimura
authors: Takato
authors: T
authors: Ueno
authors: Michio
authors: M
authors: Sata
authors: Takashi
authors: T
authors: Okamura
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005136:Eye Proteins / Q000494:pharmacology*; D006801:Humans; D009101:Multiple Myeloma / Q000098:blood supply* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009414:Nerve Growth Factors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D005136:Eye Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019255:NADPH Oxidases; D009414:Nerve Growth Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C086986:CYBA protein, human