Vascular endothelial growth factor (VEGF) is a survival and angiogenesis factor that has been the target of chemotherapy in a variety of cancers including chronic lymphocytic leukemia (CLL). The VEGF survival response is regulated by an autocrine loop where cells constitutively express VEGF and activate the VEGF receptors leading to up-regulation of anti-apoptotic Bcl-2 members and prevention of apoptosis. Herein, we have demonstrated that VEGF is elevated in the plasma of CLL patients compared to normal individuals. We have previously shown that the growth factor, lysophospatidic acid (LPA), is a survival factor in CLL and its receptor LPA1 is up-regulated in CLL cells (

J Biol Chem
,
280
:
9498
,
2005
). Now, we demonstrate that inhibiting VEGF receptor activation blocks the survival response seen with LPA in CLL. LPA treatment was found to induce VEGF mRNA and protein levels within 1 hour. LPA receptor inhibitor Ki16425 blocked the VEGF production and reversed the protective effect of LPA against apoptosis. Combining LPA and VEGF failed to increase survival responses in these cells. In addition, LPA protection against fludarabine and TRAIL induced apoptosis was eliminated using the VEGF receptor kinase inhibitor, epigallocatechin-3-gallate (EGCG), which is present in green tea, or VEGFR:Fc, that inhibits VEGF receptor activation. Furthermore, LPA induced AKT activation and up-regulation of the expression of the Bcl-2 family member, Mcl-1, were eliminated by the VEGF receptor inhibitor. Thus, the protective effect of LPA against apoptosis in CLL is related to increased production of VEGF. Targeting the LPA pathway similar to the VEGF pathway may thus be a novel approach for the treatment of CLL.

Topics:
autocrine, chronic b-cell leukemias, chronic lymphocytic leukemia, vascular endothelial growth factor a, signal pathway, signal transduction pathways, vascular endothelial growth factor receptors, angiogenesis factor, cancer, chemotherapy regimen

Disclosure: No relevant conflicts of interest to declare.

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2006, The American Society of Hematology
2006
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