5‐Lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor

5‐Lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor
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5-脂氧合酶调节恶性间皮细胞存活:血管内皮生长因子的参与

DOI:
10.1096/fj.01-0150com
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发表时间:
2001
期刊:
The FASEB Journal
影响因子:
--
通讯作者:
A. Procopio
A. Procopio
中科院分区:
--
文献类型:
--
作者:
M. Romano;A. Catalano;M. Nutini;Etrusca D'Urbano;C. Crescenzi;J. Clària;Roberta Libner;G. Davı̀;A. Procopio

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有证据表明,脂氧合酶(LO)可能在癌细胞存活中发挥作用。我们发现,人恶性胸膜间皮(MM)细胞,而不是正常间皮(NM)细胞,表达具有催化活性的5-LO。对MM细胞5-LO的药物或遗传抑制决定了核小体的形成,并诱导了典型的细胞凋亡DNA片段化。外源添加5(S)-HETE但不能被12(S)-、15(S)-HETE或白三烯(LT)B4逆转。5-LO反义寡核苷酸能有效地、时间依赖性地减少MM细胞条件培养液中血管内皮生长因子(VEGF)的表达和积聚。将5-LO基因导入NM细胞后,基础和花生四烯酸诱导的血管内皮生长因子的生成分别增加6倍和12倍。这与DNA合成的显著增加有关,这种合成被特定的抗血管内皮生长因子抗体所抵消。花生四烯酸和5(S)-HETE也能有效地刺激血管内皮生长因子启动子的活性。因此,5-LO是MM细胞增殖和存活的关键调节因子,通过与血管内皮生长因子相关的回路。-Romano,M.,Catalano,A.,Nutini,M.,D‘Urbano,E.,Cresenzi,C.,Claria,J.,Libner,R.,Davi,G.,ProCopio,A.5-Lipoxygenase调节恶性间皮细胞存活:参与血管内皮生长因子的参与。FASE B J.15,2326-2336(2001)
Evidence indicates that lipoxygenases (LO) may play a role in cancer cell survival. We show that human malignant pleural mesothelial (MM) cells, but not normal mesothelial (NM) cells, express a catalytically active 5‐LO. Pharmacological or genetic inhibition of MM cell 5‐LO determined nucleosome formation and induced a DNA fragmentation pattern typical of apoptosis. This was completely reversed by exogenously added 5(S)‐HETE but not by 12(S)‐, 15(S)‐HETE, or leukotriene (LT)B4. A 5‐LO antisense oligo‐nucleotide potently and time‐dependently reduced vascular endothelial growth factor (VEGF) mRNA and constitutive VEGF accumulation in the conditioned media of MM cells. When NM cells were transfected with a 5‐LO cDNA, basal and arachidonic acid‐induced VEGF formation increased consistently by 6‐ and 12‐fold, respectively. This was associated with a significant increase in DNA synthesis that was counteracted by a specific anti‐VEGF antibody. Arachidonic acid and 5(S)‐HETE also potently stimulated the activity of a VEGF promoter construct. Thus, 5‐LO is a key regulator of MM cell proliferation and survival via a VEGF‐related circuit.—Romano, M., Catalano, A., Nutini, M., D'Urbano, E., Crescenzi, C., Claria, J., Libner, R., Davi, G., Procopio, A. 5‐Lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor. FASEB J. 15, 2326–2336 (2001)
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