Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor.
We show that cell lines derived from childhood alveolar rhabdomyosarcoma (RMS) are very sensitive to the growth-inhibitory effects of the immunosuppressive agent rapamycin (RAP), compared to other human cell lines (50% inhibitory concentration range of 0.1-8 ng/ml, compared to 1280 to > 10,000 ng/ml). Our data suggest that the sensitivity of RMS lines is due to RAP inhibition of insulin-like growth factor 1 receptor-mediated signaling, which is essential for continued proliferation of RMS cells. The embryonal RMS line Rh1, which was resistant to RAP in serum-containing medium (50% inhibitory concentration, 4180 ng/ml), was highly sensitive under autocrine conditions of growth, indicating that resistance was due to paracrine signaling pathways insensitive to RAP action. FK506 reversed RAP action in all cell lines, indicating a dependence on complexing with the cytosolic FK506-binding protein for activity.
Dilling
M B
MB
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Dias
P
P
Shapiro
D N
DN
Germain
G S
GS
Johnson
R K
RK
Houghton
P J
PJ
D002352:Carrier Proteins / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D002648:Child; D003110:Colonic Neoplasms / Q000473:pathology*; D006360:Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D011090:Polyenes / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D012208:Rhabdomyosarcoma / Q000473:pathology*; D020123:Sirolimus; D016559:Tacrolimus / Q000494:pharmacology; D022021:Tacrolimus Binding Proteins; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; D017526:Receptor, IGF Type 1; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus