Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide.
In melanoma, the PI3K-AKT-mTOR (AKT) and RAF-MEK-ERK (MAPK) signaling pathways are constitutively activated and appear to play a role in chemoresistance. Herein, we investigated the effects of pharmacological AKT and MAPK pathway inhibitors on chemosensitivity of melanoma cells to cisplatin and temozolomide. Chemosensitivity was tested by examining effects on growth, cell cycle, survival, expression of antiapoptotic proteins, and invasive tumor growth of melanoma cells in monolayer and organotypic culture, respectively. MAPK pathway inhibitors did not significantly increase chemosensitivity. AKT pathway inhibitors consistently enhanced chemosensitivity yielding an absolute increase of cell growth inhibition up to 60% (P<0.05, combination therapy vs monotherapy with inhibitors or chemotherapeutics). Cotreatment of melanoma cells with AKT pathway inhibitors and chemotherapeutics led to a 2- to 3-fold increase of apoptosis (P<0.05, combination therapy vs monotherapy) and completely suppressed invasive tumor growth in organotypic culture. These effects were associated with suppression of the antiapoptotic Bcl-2 family protein Mcl-1. These data suggest that inhibition of the PI3K-AKT-mTOR pathway potently increases sensitivity of melanoma cells to chemotherapy.
Sinnberg
Tobias
T
Division of Dermatologic Oncology, Department of Dermatology, University of Tuebingen, Tuebingen, Germany.
Lasithiotakis
Konstantinos
K
Niessner
Heike
H
Schittek
Birgit
B
Flaherty
Keith T
KT
Kulms
Dagmar
D
Maczey
Evelyn
E
Campos
Minia
M
Gogel
Jeannette
J
Garbe
Claus
C
Meier
Friedegund
F
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D002945:Cisplatin; D003606:Dacarbazine; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D058570:TOR Serine-Threonine Kinases; D000077204:Temozolomide; C546842:MTOR protein, human