title: Lysophosphatidic acid (LPA) protects primary chronic lymphocytic leukemia cells from apoptosis through LPA receptor activation of the anti-apoptotic protein AKT/PKB.
abstract: Lysophosphatidic acid (LPA) protects epithelial and fibroblast cell lines from apoptosis. In B-cells, LPA acts as a growth factor promoting cell proliferation. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD19+/CD5+ B-lymphocytes primarily through a block in apoptosis. The mechanisms underlying this defect are not fully understood. We investigated whether LPA could be a survival factor in CLL cells. Herein, we demonstrate that LPA protects B-cell lines BJAB and I-83 and primary CLL cells but not normal B-cells from fludarabine- and etoposide-induced apoptosis. Furthermore, LPA prevented spontaneous apoptosis in primary CLL cells. The LPA1 expression was found to be increased in primary CLL cells compared with normal B-cells correlating with LPA prevention of apoptosis. Treatment of primary CLL cells with the LPA receptor antagonist, diacylglycerol pyrophosphate, reverses the protective effect of LPA against apoptosis, and down-regulation of the LPA1 by siRNA blocked LPA-mediated protection against spontaneous apoptosis in primary CLL cells. The protective effect of LPA was inhibited by blocking activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. These results indicate that LPA is a survival factor in B-cell lines and primary CLL cells but not normal B-cells. Thus, drugs targeting the LPA receptors might be an effective therapy against B-cell-derived malignancies such as CLL.
authors.affiliation: Manitoba Institute of Cell Biology and the Department of Pediatrics, University of Manitoba, Winnipeg, Manitoba R3E 0V9, Canada.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Hu
authors.forename: Neil
authors.initials: N
authors.lastname: Haney
authors.forename: Dianne
authors.initials: D
authors.lastname: Kropp
authors.forename: Albert F
authors.initials: AF
authors.lastname: Kabore
authors.forename: James B
authors.initials: JB
authors.lastname: Johnston
authors.forename: Spencer B
authors.initials: SB
authors.lastname: Gibson
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000097:blood*; D011518:Proto-Oncogene Proteins / Q000097:blood*; D051057:Proto-Oncogene Proteins c-akt; D049368:Receptors, Lysophosphatidic Acid / Q000097:blood* / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D008246:Lysophospholipids; D011518:Proto-Oncogene Proteins; D049368:Receptors, Lysophosphatidic Acid; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D014740:Vidarabine; C024352:fludarabine; C032881:lysophosphatidic acid