The magnitude of Akt/phosphatidylinositol 3'-kinase proliferating signaling is related to CD45 expression in human myeloma cells.
In multiple myeloma, the Akt/PI3K pathway is involved in the proliferation of myeloma cells. In the current study, we have investigated the impact of the CD45 phosphatase in the control of Akt/PI3K activation. We show that Akt activation in response to insulin-like growth factor-1 (IGF-1) is highly variable from one human myeloma cell line to another one. Actually, Akt activation is highly related to whether CD45 is expressed or not. Indeed, both the magnitude and the duration of Akt phosphorylation in response to IGF-1 are more important in CD45- than in CD45+ myeloma cell lines. We next demonstrate a physical association between CD45 and IGF-1 receptor (IGF-1R) suggesting that CD45 could be involved in the dephosphorylation of the IGF-1R. Furthermore, the growth of CD45- myeloma cell lines is mainly or even totally controlled by the PI3K pathway whereas that of CD45+ myeloma cell lines is modestly controlled by it. Indeed, wortmannin, a specific PI3K inhibitor, induced a dramatic growth inhibition in the CD45- myeloma cell lines characterized by a G1 growth arrest, whereas it has almost no effect on CD45+ myeloma cell lines. Altogether, these results suggest that CD45 negatively regulates IGF-1-dependent activation of PI3K. Thus, strategies that block IGF-1R signaling and consequently the Akt/PI3K pathway could be a priority in the treatment of patients with multiple myeloma, especially those lacking CD45 expression that have a very poor clinical outcome.
Institut National de la Santé et de la Recherche Médicale Unité 601, Ligue Nationale contre le Cancer Label, Nantes, France.
Géraldine
G
Descamps
Catherine
C
Pellat-Deceunynck
Yann
Y
Szpak
Régis
R
Bataille
Nelly
N
Robillard
Martine
M
Amiot
D000730:Androstadienes / Q000494:pharmacology; D002455:Cell Division; D045744:Cell Line, Tumor; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000032:analysis*; D009101:Multiple Myeloma / Q000737:chemistry / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D014638:Vanadates / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D007334:Insulin-Like Growth Factor I; D017493:Leukocyte Common Antigens; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D014638:Vanadates; D000077191:Wortmannin; C076715:pervanadate; C494918:AKT1 protein, human