Involvement of FKHRL1 in melanoma cell survival and death.
Melanoma is a highly aggressive tumour characterized by a strong resistance to apoptotic stimuli that give rise to a selective advantage for tumour progression and metastasis formation. Therefore, it is of paramount importance to better understand the mechanisms involved in this resistance to apoptosis. In this report, we focused our attention on FKHRL1, a member of the forkhead family of transcription factors, which controls expression of genes involved in cell cycle progression and apoptosis. In melanoma cells, we show that IGF1, which exerts pro-survival properties, induces the phosphorylation and nuclear exclusion of FKHRL1 in a PI3K/AKT-dependent pathway. Moreover, we observe that over-expression of a non-phosphorylable mutant of FKHRL1 (FKHRL1-TM), constitutively localized to the nucleus, promotes apoptotic cell death of melanoma cells. Finally, we find that FKHRL1-TM decreases the expression of survivin, a member of the inhibitor of apoptosis protein and that survivin re-expression partially rescues the deleterious effects of FKHRL1. Taken together, these findings reveal, in melanoma cells, that endogenous FKHRL1 is a downstream target of the PI3K/AKT pathway and suggest that the phosphorylation of this transcription factor may be involved in the pro-survival effects of growth factors such as IGF1. On the other hand, forced nuclear localization of FKHRL1 decreases melanoma cell growth and may serve as a therapeutic strategy against melanoma.
Hilmi
C
C
INSERM U597, Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée au mélanome, Nice, France.
Larribere
L
L
Deckert
M
M
Rocchi
S
S
Giuliano
S
S
Bille
K
K
Ortonne
J P
JP
Ballotti
R
R
Bertolotto
C
C
D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D000077022:Survivin
C107489:BIRC5 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D007334:Insulin-Like Growth Factor I