Lysophosphatidic acid (LPA) induces the expression of VEGF leading to protection against apoptosis in B-cell derived malignancies.
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.
Hu
Xiaojie
X
Manitoba Institute of Cell Biology, Winnipeg, MB, Canada.
Mendoza
Francisco J
FJ
Sun
Jinmie
J
Banerji
Versha
V
Johnston
James B
JB
Gibson
Spencer B
SB
D017209:Apoptosis; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000378:metabolism*; D008246:Lysophospholipids / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism; D009153:Mutagens / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D014740:Vidarabine / Q000031:analogs & derivatives / Q000633:toxicity
D008246:Lysophospholipids; D009153:Mutagens; D016328:NF-kappa B; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D048031:JNK Mitogen-Activated Protein Kinases; D014740:Vidarabine; C024352:fludarabine; C032881:lysophosphatidic acid