Human colorectal adenocarcinoma cells: differential nitric oxide synthesis determines their ability to aggregate platelets.
The existence and role of an L-arginine:nitric oxide (NO) pathway in two human colorectal adenocarcinoma cell lines, SW-480 and SW-620, were investigated. Both cell lines, which derive from the same patient, SW-480 from the primary tumor and SW-620 from its metastatic lesion, were shown to have a cytosolic, Ca(2+)-independent, NADPH-dependent NO synthase, the activity of which was lower in the cytosol of SW-620. These cells were more potent inducers of platelet aggregation. In contrast, SW-480, which had more NO synthase activity, were less potent inducers of platelet aggregation. Pretreatment of both cell lines with NG-monomethyl-L-arginine, an inhibitor of NO synthase, potentiated their proaggregating effect and made them equally active. Exogenous L-arginine, NO, and related nitrovasodilators all inhibited platelet aggregation induced by SW-620. The antiaggregating activity of NO was further potentiated by prostacyclin and by M&B22948, a selective inhibitor of cyclic GMP phosphodiesterase. We propose that the generation of NO by tumor cells inversely correlates with their metastatic potential. Furthermore, we show that the lower activity of NO synthase in metastatic cells is due to the presence in these cells of a low molecular weight inhibitor of the NO synthase. In addition, agents which modulate platelet function by a cyclic GMP-dependent mechanism may be useful in the prevention of tumor metastasis.
Radomski
M W
MW
Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Jenkins
D C
DC
Holmes
L
L
Moncada
S
S
D000230:Adenocarcinoma / Q000097:blood* / Q000473:pathology; D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000097:blood* / Q000473:pathology; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase; D010974:Platelet Aggregation / Q000187:drug effects; D011688:Purinones / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine
D011688:Purinones; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C011145:zaprinast