mTOR is activated in the majority of malignant melanomas.
The objective of this study was to determine whether activation of the kinase mammalian target of rapamycin (mTOR) is associated with human melanoma. We found moderate or strong hyperphosphorylation of ribosomal protein S6 in 78/107 melanomas (73%). In contrast, only 3/67 benign nevi (4%) were moderately positive, and none were strongly positive. These data indicate that mTOR activation is very strongly associated with malignant, compared to benign, melanocytic lesions. Next, we tested six melanoma-derived cell lines for evidence of mTOR dysregulation. Five of the six lines showed persistent phosphorylation of S6 after 18 hours of serum deprivation, and four had S6 phosphorylation after 30 minutes of amino-acid withdrawal, indicating inappropriate mTOR activation. The proliferation of three melanoma-derived lines was blocked by the mTOR inhibitor rapamycin, indicating that mTOR activation is a growth-promoting factor in melanoma-derived cells. mTOR is directly activated by the small guanosine triphosphatase Ras homolog enriched in brain (Rheb), in a farnesylation-dependent manner. Therefore, to investigate the mechanism of mTOR activation, we used the farnesyl transferase inhibitor FTI-277, which partially blocked the growth of three of the six melanoma cell lines. Together, these data implicate activation of mTOR in the pathogenesis of melanoma, and suggest that Rheb and mTOR may be targets for melanoma therapy.
Karbowniczek
Magdalena
M
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Spittle
Cynthia S
CS
Morrison
Tasha
T
Wu
Hong
H
Henske
Elizabeth P
EP
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D009506:Nevus / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D038601:Ribosomal Protein S6 / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D058570:TOR Serine-Threonine Kinases
D047428:Protein Kinase Inhibitors; D038601:Ribosomal Protein S6; D011494:Protein Kinases; C546842:MTOR protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D020123:Sirolimus