Molecular identification, localization and function of platelet-type 12-lipoxygenase in human melanoma progression, under experimental and clinical conditions.
As previous studies suggested the expression of a 12-LOX enzyme in murine and human melanoma cell lines, the primary aim of this project was to genetically identify the 12-LOX enzyme (platelet-, leukocyte- or epithelial form). By using reverse transcriptase-polymerase chain reaction, sequencing and various immunological techniques we have demonstrated conclusively the expression of the platelet-type 12-LOX in human melanoma cells of different origin, in their transplanted xenografts and in fresh human skin tumors. Furthermore, we found that p12-LOX is able to provide a survival signal for melanoma cells since inhibition of the enzyme by general LOX or selective 12-LOX inhibitors induced apoptosis in vitro. p12-LOX of human melanoma has been shown to be involved in the control of the metastatic phenotype, since we have detected the upregulation of the 12-LOX protein expression in spontaneously metastasizing xenografts and in thick human skin tumors (> 3.0 mm) characterized by high risk for the development of metastasis. Co-expression of two megakaryocytic genes, p12-LOX and alphaIIb integrin chains, was found to be a frequent phenomenon in human melanoma (approximately 70%) suggesting a common regulatory defect in this tumor.
Department of Tumor Progression, National Institute of Oncology, Budapest, Hungary.
Erzsébet
E
Rásó
Balázs
B
Döme
Beáta
B
Somlai
Alex
A
Zacharek
Wolfgang
W
Hagmann
Kenneth V
KV
Honn
József
J
Tímár
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001792:Blood Platelets / Q000201:enzymology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D016023:Integrins; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis / Q000473:pathology; D009368:Neoplasm Transplantation; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous / Q000473:pathology
D004791:Enzyme Inhibitors; D016023:Integrins; D040201:Platelet Membrane Glycoprotein IIb; D001092:Arachidonate 12-Lipoxygenase