Direct and tumor microenvironment mediated influences of 5'-deoxy-5'-(methylthio)adenosine on tumor progression of malignant melanoma.
Recent studies have shown that a loss of methylthioadenosine phosphorylase (MTAP) gene expression exerts a tumor-promoting effect, including induction of invasiveness, enhanced cell proliferation, and resistance against cytokines. To date, the molecular mechanisms underlying these effects remain unknown. Since the loss of MTAP expression resulted in induced secretion of 5'-deoxy-5'-(methylthio)adenosine (MTA), we hypothesized that MTA might modulate the observed effects. We first determined MTA levels produced by tumor cells in vitro and in situ by means of stable isotope dilution liquid chromatography tandem mass spectrometry. Subsequently, we revealed induction of matrix metalloproteinase (MMP) and growth factor gene expression in melanoma cells accompanied by enhanced invasion and vasculogenic mimicry. In addition, MTA induced the secretion of basis fibroblast growth factor (bFGF) and MMP3 from fibroblasts and the upregulation of activator protein-1 (AP-1) activity in melanoma cells and fibroblasts. In summary, we demonstrated a tumor-supporting role of MTA.
Stevens
Axel P
AP
Institute of Functional Genomics, University of Regensburg Medical School, Josef-Engert-Str. 9, D-93053 Regensburg, Germany.
Spangler
Barbara
B
Wallner
Susanne
S
Kreutz
Marina
M
Dettmer
Katja
K
Oefner
Peter J
PJ
Bosserhoff
Anja K
AK
D003839:Deoxyadenosines / Q000494:pharmacology*; D018450:Disease Progression; D005347:Fibroblasts; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013872:Thionucleosides / Q000494:pharmacology*
D003839:Deoxyadenosines; D013872:Thionucleosides; C008500:5'-methylthioadenosine