Inhibitors of polyamine biosynthesis decrease the expression of the metalloproteases meprin alpha and MMP-7 in hormone-independent human breast cancer cells.
Inhibition of ornithine decarboxylase (ODC), a key enzyme in polyamine biosynthesis, by the irreversible inhibitor alpha-difluoromethylornithine (DFMO) has been shown to decrease the invasiveness of metastatic human breast cancer cell lines. However, the mechanism by which DFMO acts to reduce invasiveness is unclear. Using the human breast cancer cell line MDA-MB-435, the effect of DFMO on metalloprotease gene expression was investigated. DFMO treatment decreases the expression of the metalloprotease meprin alpha, while concurrent treatment with DFMO and the polyamine putrescine partially restored meprin alpha expression levels. Expression of MMP-7 mRNA was reduced by DFMO, while MMPs-1, -2, -3, -14, and meprin beta were unaffected. Treatment of cells with a second inhibitor of polyamine biosynthesis, the S-adenosylmethionine decarboxylase (SAMDC) inhibitor SAM486A, also resulted in a dosage dependent decrease in meprin alpha and MMP-7 mRNA. In addition, DFMO treatment decreased meprin alpha at the protein level by 2 days of treatment, and MMP-7 protein levels at 4 and 6 days. Previous studies have shown that DFMO treatment increases ERK phosphorylation and signaling through the MAP kinase pathway. The decrease in meprin alpha expression was reversed with the MEK inhibitor PD98059, demonstrating that MAP kinase signaling mediates the effect of DFMO and SAM486A. MDA-MB-435 cells treated with the meprin alpha inhibitor actinonin (5 nM) were less invasive in vitro, indicating that meprin alpha is mechanistically involved in invasion. The decrease in meprin alpha expression in DFMO and SAM486A-treated cells indicates a means by which these compounds can decrease the invasiveness of metastatic breast cancer cells.
Matters
Gail L
GL
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, H171, Hershey, PA 17033-0850, USA.
Manni
Andrea
A
Bond
Judith S
JS
D000578:Amidines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D015536:Down-Regulation; D000518:Eflornithine / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology*; D020783:Matrix Metalloproteinase 7 / Q000235:genetics* / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009361:Neoplasm Invasiveness; D065108:Ornithine Decarboxylase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011073:Polyamines / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
D000578:Amidines; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D006877:Hydroxamic Acids; D007189:Indans; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D012333:RNA, Messenger; C082408:4-amidinoindan-1-one 2'-amidinohydrazone; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D008666:Metalloendopeptidases; C053833:meprin A; D020783:Matrix Metalloproteinase 7; C010531:actinonin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000518:Eflornithine