Tryptophan protects human melanoma cells against gamma-interferon and tumour necrosis factor-alpha: a unifying mechanism of action.
The sensitivity and resistance of six human melanoma cell lines to gamma-interferon (gamma-IFN) and tumour necrosis factor-alpha (TNF-alpha) have been examined. Amelanotic cell lines were more sensitive to gamma-IFN and TNF-alpha than melanotic cells. The cytotoxicity of gamma-IFN and TNF-alpha could be reversed in all cells by the addition of L- or D-tryptophan to the culture medium. Melanoma cells resistant to gamma-IFN excrete calcium activated neutral protease (CANP) and as a consequence, make L-tryptophan available by the hydrolysis of serum proteins in the culture medium. Resistance to gamma-IFN could be reversed by the addition of specific CANP inhibitor, whereas gamma-IFN-sensitive strains became more resistant with the addition of CANP to the culture medium. It has been confirmed that gamma-IFN induces indoleamine 2,3-dioxygenase in melanoma cells. This enzyme utilizes the superoxide anion (O2-) as a substrate for the oxidation of either L- or D-tryptophan to N-formylkynurenic acid leading to cell death. The induction of this degradative pathway for L-tryptophan kills cells by starvation of this essential and relatively scarce amino acid. TNF-alpha induces manganese-containing superoxide dismutase (MnSOD) which also uses O2- to produce cytotoxic concentrations of hydrogen peroxide. Therefore, it can be concluded that the cytotoxicity of both gamma-IFN and TNF-alpha depends on the availability of L-tryptophan as the substrate for the removal of O2- via indoleamine 2,3-dioxygenase.
Wood
J M
JM
Gray Freshwater Biological Institute, Navarre, MN 55392.
Ehrke
C
C
Schallreuter
K U
KU
D001798:Blood Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008545:Melanoma / Q000473:pathology*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014364:Tryptophan / Q000494:pharmacology*; D014366:Tryptophan Oxygenase / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D001798:Blood Proteins; D009363:Neoplasm Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D002154:Calpain; D010100:Oxygen