Hu Xiaojie, Mendoza Francisco J, Sun Jinmie, Banerji Versha, Johnston James B, Gibson Spencer B
Manitoba Institute of Cell Biology, Winnipeg, MB, Canada.
Cell Signal. 2008 Jun;20(6):1198-208. doi: 10.1016/j.cellsig.2008.02.009. Epub 2008 Feb 19.
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 NFkappaB since blocking JNK or NFkappaB 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 NFkappaB 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.
血管内皮生长因子（VEGF）是一种生存和血管生成因子，是多种癌症治疗的靶点。在许多血液系统恶性肿瘤中，VEGF的产生增加，导致细胞存活反应。在此，我们证明溶血磷脂酸（LPA）可诱导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中VEGF的mRNA表达。BJAB和I-83细胞中VEGF mRNA水平的这种增加与VEGF启动子的荧光素酶活性增加以及I-83细胞中蛋白质水平增加相对应。LPA处理后，这些细胞中VEGF的分泌也增加。LPA处理还导致VEGFR1和VEGFR2的激活。LPA诱导的VEGF表达增加是由c-Jun氨基末端激酶（JNK）和转录因子NFκB的激活介导的，因为阻断JNK或NFκB激活可抑制LPA诱导的VEGF表达。此外，我们证明LPA可保护细胞免于凋亡，使用VEGF受体激酶抑制剂阻断VEGFR1和VEGFR2的激活可阻止LPA的存活反应。敲低VEGFR1的表达并抑制NFκB和JNK的激活也可阻断LPA诱导的抗凋亡作用。综上所述，这表明LPA在B细胞恶性肿瘤中促进VEGF的产生，从而导致细胞存活。
