Roles of stem cell factor/c-Kit and effects of Glivec/STI571 in human uveal melanoma cell tumorigenesis.
The B-Raf(V599E)-mediated constitutive activation of ERK1/2 is involved in establishing the transformed phenotype of some uveal melanoma cells (Calipel, A., Lefevre, G., Pouponnot, C., Mouriaux, F., Eychene, A., and Mascarelli, F. (2003) J. Biol. Chem. 278, 42409-42418). We have shown that stem cell factor (SCF) is involved in the proliferation of normal uveal melanocytes and that c-Kit is expressed in 75% of primary uveal melanomas. This suggests that the acquisition of autonomous growth during melanoma progression may involve the SCF/c-Kit axis. We used six human uveal melanoma tumor-derived cell lines and normal uveal melanocytes to characterize the SCF/c-Kit system and to assess its specific role in transformation. We investigated the possible roles of activating mutations in c-KIT, the overexpression of this gene, and ligand-dependent c-Kit overactivation in uveal melanoma cell tumorigenesis. Four cell lines (92.1, SP6.5, Mel270, and TP31) expressed both SCF and c-Kit, and none harbored the c-KIT mutations in exons 9, 11, 13, and 17 that have been shown to induce SCF-independent c-Kit activation. Melanoma cell proliferation was strongly inhibited by small interfering RNA-mediated depletion of c-Kit in these cells, despite the presence of (V599E)B-Raf in SP6.5 and TP31 cells. We characterized the signaling pathways involved in SCF/c-Kit-mediated cell growth and survival in normal and tumoral melanocytes and found that constitutive ERK1/2 activation played a key role in both the SCF/c-Kit autocrine loop and the gain of function of (V599E)B-Raf for melanoma cell proliferation and transformation. We also provide the first evidence that Glivec/STI571, a c-Kit tyrosine kinase inhibitor, could be used to treat uveal melanomas.
Lefevre
Gaëlle
G
INSERM U598, Institut Biomédical des Cordeliers, 75006 Paris, France.
Glotin
Anne-Lise
AL
Calipel
Armelle
A
Mouriaux
Frédéric
F
Tran
Thi
T
Kherrouche
Zoulika
Z
Maurage
Claude-Alain
CA
Auclair
Christian
C
Mascarelli
Frédéric
F
D001483:Base Sequence; D001549:Benzamides; D002455:Cell Division; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D008544:Melanocytes / Q000502:physiology; D008545:Melanoma / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D008934:Mitogens / Q000378:metabolism; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D011743:Pyrimidines / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics / Q000502:physiology*; D014602:Uvea / Q000502:physiology; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology
D001549:Benzamides; D017931:DNA Primers; D008934:Mitogens; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit