Matrix metalloproteinase 2 in tumor cell-induced platelet aggregation: regulation by nitric oxide.
A correlation exists between the ability of tumor cells to aggregate platelets and their tendency to metastasize. Tumor cell-induced platelet aggregation (TCIPA) facilitates the embolization of the vasculature with tumor cells and the formation of metastatic foci. It is well documented that matrix metalloproteinases (MMPs) play an integral part in tumor spread and the metastatic cascade. Therefore, we have examined the role of MMPs during TCIPA and its regulation by nitric oxide (NO) in vitro. Human HT-1080 fibrosarcoma and A549 lung epithelial cancer cells induced TCIPA in a concentration-dependent manner that was monitored by aggregometry. This aggregation resulted in the release of MMIP-2 from platelets and cancer cells, as measured by zymography. HT-1080 cells released significantly more MMP-2 than A549 cells and were more efficacious in inducing TCIPA. Inhibition of MMP-2 with phenanthroline (1-1000 microM), a synthetic inhibitor of MMPs, and by neutralizing anti-MMIP-2 antibody (10 microg/ml) reduced TCIPA induced by HT-1080 cells. TCIPA was abolished by simultaneous inhibition of platelet function with acetylsalicylic acid (100 microM; thromboxane pathway inhibitor), apyrase (250 microg/ml; ADP pathway inhibitor), and phenanthroline. NO donors such as S-nitroso-n-acetylpenicillamine and S-nitrosoglutathione (both at 0.01-100 microM) inhibited TCIPA and MMP-2 release from platelets and tumor cells. The inhibitory actions of S-nitroso-n-acetylpenicillamine and S-nitrosoglutathione were reversed by 1H-[1,2,4]oxadiazole[4,3]quinoxalin-1-one (0.01-30 microM), a selective inhibitor of the soluble guanylyl cyclase. We conclude that (a) human fibrosarcoma cells aggregate platelets via mechanism(s) that are mediated, in part, by MMP-2; (b) NO inhibits TCIPA, in part, by attenuating the release of MMP-2; and (c) these effects of NO are cGMP-dependent.
Jurasz
P
P
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Sawicki
G
G
Duszyk
M
M
Sawicka
J
J
Miranda
C
C
Mayers
I
I
Radomski
M W
MW
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000502:physiology; D001792:Blood Platelets / Q000166:cytology / Q000201:enzymology; D002450:Cell Communication / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000494:pharmacology; D005354:Fibrosarcoma / Q000201:enzymology / Q000473:pathology; D018093:Gelatinases / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine; D026422:S-Nitrosoglutathione; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000502:physiology; D014407:Tumor Cells, Cultured
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D010069:Oxadiazoles; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D011810:Quinoxalines; C076847:cyclo(acetylpenicillamyl-arginyl-glycyl-aspartyl-cysteinamide); D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D026423:S-Nitroso-N-Acetylpenicillamine; D011464:Epoprostenol; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D005978:Glutathione; D010396:Penicillamine