Suppression of mTOR complex 2-dependent AKT phosphorylation in melanoma cells by combined treatment with rapamycin and LY294002

Summary Background  Inhibition of mTOR complex 1 (mTORC1) with rapamycin leads to phosphorylation of AKT in some cancer cells, with unknown biological consequences. The role of this phosphorylation in melanoma is unknown, although preliminary clinical data indicate poor activity of rapalogues in mel...

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Bibliographic Details
Published in:British journal of dermatology (1951) 2009-05, Vol.160 (5), p.955-964
Main Authors: Werzowa, J., Cejka, D., Fuereder, T., Dekrout, B., Thallinger, C., Pehamberger, H., Wacheck, V., Pratscher, B.
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Biological and medical sciences
Blotting, Western
Cell Cycle - drug effects
Cell Line, Tumor
Chromones - therapeutic use
Dermatology
Drug Therapy, Combination
Humans
LY294002
Medical sciences
melanoma
Melanoma - drug therapy
Melanoma - metabolism
Morpholines - therapeutic use
mTORC1
mTORC2
Phosphorylation - drug effects
Proto-Oncogene Proteins c-akt - drug effects
rapamycin
Reverse Transcriptase Polymerase Chain Reaction
Sirolimus - therapeutic use
Skin Neoplasms - drug therapy
Skin Neoplasms - metabolism
Transcription Factors - antagonists & inhibitors
Tumors of the skin and soft tissue. Premalignant lesions
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Summary:Summary Background  Inhibition of mTOR complex 1 (mTORC1) with rapamycin leads to phosphorylation of AKT in some cancer cells, with unknown biological consequences. The role of this phosphorylation in melanoma is unknown, although preliminary clinical data indicate poor activity of rapalogues in melanoma. Objectives  We aimed at elucidating the role of AKT phosphorylation after mTORC1 inhibition in melanoma cells. Methods  Western blotting, apoptosis assays, cell cycle analyses and viability assays were performed to analyse the effects of rapamycin and LY294002 treatment on melanoma cells. For suppression of mTOR complex 2 (mTORC2) an siRNA directed against rictor was used. Results  Rapamycin showed limited effects on cell viability but resulted in strong and lasting AKT phosphorylation in melanoma cells. Combined PI3K/mTOR inhibition with LY294002 had pronounced effects on viability but also led to increased AKT phosphorylation after prolonged treatment. In contrast, combination of rapamycin plus LY294002 suppressed AKT phosphorylation. Suppression of AKT phosphorylation did not correlate with decreases in cell viability. Inhibition of mTORC2 led to reduced levels of phosphorylated AKT. Conclusions  mTORC1 inhibition with rapamycin and with LY294002 can lead to AKT phosphorylation in melanoma cells via mTORC2. Combination of rapamycin and LY294002 suppresses AKT phosphorylation but without significant effect on treatment efficacy.
ISSN:0007-0963
1365-2133
DOI:10.1111/j.1365-2133.2008.08991.x