Lysophosphatidic acid (LPA) induces the expression of VEGF leading to protection against apoptosis in B-cell derived malignancies
Lysophosphatidic acid (LPA) induces the expression of VEGF leading to protection against apoptosis in B-cell derived malignancies
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DOI：
10.1016/j.cellsig.2008.02.009
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发表时间：
2008-06-01
影响因子：
4.8
通讯作者：
Gibson, Spencer B.
中科院分区：
文献类型：
--
作者：
Hu, Xiaojie;Mendoza, Francisco J.;Gibson, Spencer B.
血管内皮生长因子（VEGF）是一种存活和血管生成因子，是多种癌症治疗的靶点。在许多血液恶性肿瘤中，VEGF的产生增加，导致细胞生存反应。在此，我们证明，溶血磷脂酸（LPA）诱导VEGF在多发性骨髓瘤细胞系，U266，伯基特淋巴瘤细胞系，BJAB，和慢性淋巴细胞白血病（CLL）样细胞系，I-83的mRNA表达。VEGF mRNA水平的增加与BJAB和I-83细胞中VEGF启动子的荧光素酶活性增加以及I-83细胞中蛋白水平增加相对应。LPA处理后，这些细胞中VEGF的分泌也增加。LPA治疗还导致VEGFR 1和VEGFR 2的激活。由于阻断JNK或NF κ B活化抑制LPA诱导的VEGF表达，因此LPA诱导的VEGF表达的增加由c-Jun N-末端激酶（JNK）和转录因子NF κ B的活化介导。此外，我们已经证明LPA保护细胞免于凋亡，并且使用VEGF受体激酶抑制剂阻断VEGFR 1和VEGFR 2的激活防止了LPA存活应答。下调VEGF 1的表达，抑制NF κ B B和JNK的活化，也可阻断LPA诱导的细胞凋亡保护作用。总之，这表明LPA有助于B细胞恶性肿瘤中VEGF的产生，从而导致细胞存活。(C)2008年爱思唯尔公司All rights reserved.
Vascular endothelial growth factor (VEGF) is a survival and angiogenesis factor that is a target for therapy in a variety of cancers. In many hematological malignancies, VEGF production is increased leading to cell survival responses. Herein, we demonstrate that lysophosphatidic acid (LPA) induces mRNA expression of VEGF in the multiple myeloma cell line, U266, the Burkitt's lymphoma cell line, BJAB, and the chronic lymphocytic leukemia (CLL)-like cell line, I-83. This increase in mRNA levels of VEGF corresponded with increased luciferase activity of the VEGF promoter in BJAB and I-83 cells and increased protein levels in I-83 cells. Secretion of VEGF was also increased in these cells following LPA treatment. LPA treatment also caused the activation of both VEGFR1 and VEGFR2. The increase in VEGF expression by LPA is mediated by the activation of c-Jun N-terminal Kinase (JNK) and transcription factor NF kappa B since blocking JNK or NF kappa B activation inhibited LPA induced VEGF expression. Furthermore, we have demonstrated that LPA protects cells from apoptosis and blocking activation of both VEGFR1 and VEGFR2 using a VEGF receptor kinase inhibitor prevented LPA survival responses. Knocking down expression of VEGFR1 and inhibiting activation of NF kappa B and JNK also blocked LPA induced protection against apoptosis. Taken together, this indicates that LPA contributes to VEGF production in B cell malignancies leading to cell survival. (C) 2008 Elsevier Inc. All rights reserved.