VEGF165 promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition
VEGF165 promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition
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DOI：
10.1182/blood.v99.7.2532
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发表时间：
2002-04-01
期刊：
影响因子：
20.3
通讯作者：
Rafii, S
中科院分区：
文献类型：
--
作者：
Dias, S;Shmelkov, SV;Rafii, S
与内皮细胞（ECs）类似，血管内皮生长因子（VEGF）在VEGF受体阳性（VEGFR(+)）原发性白血病和细胞系上诱导Bcl-2表达，促进生存。我们通过对VEGF处理和未处理的HL-60白血病细胞进行基因表达分析，研究了VEGF在这种白血病中激活的分子途径。VEGF刺激后增加的一个基因是热休克蛋白90 （Hsp90）。随后在蛋白水平上，在原发性白血病和白血病细胞系上证实了这一点。VEGF通过与KDR相互作用，激活丝裂原激活的蛋白激酶级联，增加Hsp90的表达。反过来，Hsp90调节Bcl-2的表达，如vegif诱导的Bcl-2表达完全阻断和Hsp90特异性抑制剂格尔达霉素（GA）与Hsp90的结合所示。GA还阻断了vegf诱导的Hsp90与白血病细胞上APAF-11的结合，这是一种抑制细胞凋亡的机制。值得注意的是，VEGF阻断了GA的促凋亡作用，这与其在分子水平上的作用有关。早些时候，我们发现在一些白血病中，VEGF/KDR自分泌环对细胞存活至关重要，而在这里，我们确定了这种作用的分子相关。我们还证明，在VEGFR+细胞（如ECs）上产生VEGF/VEGFR自分泌环也可以保护它们免于凋亡。表达VEGF的腺病毒感染内皮细胞导致Hsp90水平升高，Bel-2表达增加，并对无血清或ga诱导的细胞凋亡产生抗性。总之，我们证明了Hsp90介导VEGF的抗凋亡和促生存作用，这可能有助于VEGFR+细胞（如白血病亚群）的生存优势。（血液。2002;99:2532-2540）(C) 2002由美国血液学会。
Similar to endothelial cells (ECs), vascular endothelial growth factor (VEGF) induces Bcl-2 expression on VEGF receptorpositive (VEGFR(+)) primary leukemias and cell lines, promoting survival. We investigated the molecular pathways activated by VEGF on such leukemias, by performing a gene expression analysis of VEGF-treated and untreated HL-60 leukemic cells. One gene to increase after VEGF stimulation was heat shock protein 90 (Hsp90). This was subsequently confirmed at the protein level, on primary leukemias and leukemic cell lines. VEGF increased the expression of Hsp90 by interacting with KDR and activating the mitogen-activated protein kinase cascade. In turn, Hsp90 modulated Bcl-2 expression, as shown by a complete blockage of VEGIF-induced Bcl-2 expression and binding to Hsp90 by the Hsp90-specific inhibitor geldanamycin (GA). GA also blocked the VEGF-Induced Hsp90 binding to APAF-11 on leukemic cells, a mechanism shown to inhibit apoptosis. Notably, VEGF blocked the proapoptotic effects of GA, correlating with its effects at the molecular level. Earlier, we showed that in some leukemias, a VEGF/KDR autocrine loop is essential for cell survival, whereas here we identified the molecular correlates for such an effect. We also demonstrate that the generation of a VEGF/VEGFR autocrine loop on VEGFR+ cells such as ECs, also protected them from apoptosis. Infection of ECs with adenovirus-expressing VEGF resulted in elevated Hsp90 levels, increased Bel-2 expression, and resistance to serum-free or GA-induced apoptosis. In summary, we demonstrate that Hsp90 mediates antiapoptotic and survival-promoting effects of VEGF, which may contribute to the survival advantage of VEGFR+ cells such as subsets of leukemias. (Blood. 2002;99: 2532-2540) (C) 2002 by The American Society of Hematology.