Bombesin-dependent pro-MMP-9 activation in prostatic cancer cells requires beta1 integrin engagement.
Bombesin-like peptides, including the mammalian homologue gastrin-releasing peptide, are highly expressed and secreted by neuroendocrine cells in prostate carcinoma tissues and are likely to be related to the progression of this neoplastic disease. Previously, we demonstrated that bombesin increased migration and protease expression in androgen-independent cells. In this work we show that bombesin is able to activate pro-MMP-9 through a mechanism involving the beta1 integrin subunit. In fact, MMP-9 processing was evident only when beta1 integrin was engaged with specific adhesive substrates, such as type I collagen, or when cells were seeded on dishes coated with antibodies against beta1 integrin, resulting in activation of the surface ligand. When exogenous pro-MMP-9 was added to PC3 cells, MMP-9 active forms were produced within 30 min by bombesin-treated cultures while control cultures expressed activated forms only after a longer time and at lower levels. MMP-9 activation required cytoskeleton integrity since this effect was abolished by cytochalasin D. Engagement of beta1 integrin caused an increased membrane-linked uPA activity which was required for MMP-9 activation. The cross talk between bombesin- and beta1-integrin-engaged signals seems to be crucial for the modulation of both membrane-linked uPA activity and MMP-9 activation and triggers complex intracellular signaling pathways requiring activation of tyrosine kinase activity, including that of src and PI3K. The beta1 integrin may be considered an important mechanism by which bombesin induces MMP-9 activation. This finding supports the idea that cellular responses to growth factors may be driven by cell-matrix interactions and stresses the role of neuroendocrine factors in prostate carcinoma progression.
Festuccia
Claudio
C
Department of Experimental Medicine, University of L'Aquila, Italy. festucci@univaq.it
Angelucci
Adriano
A
Gravina
Giovanni
G
Eleuterio
Enrica
E
Vicentini
Carlo
C
Bologna
Mauro
M
D001839:Bombesin / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism*; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D008297:Male; D020780:Matrix Metalloproteinase 9; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010958:Plasminogen / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D005343:Fibrinolytic Agents; D019012:Integrin beta1; D019384:Nucleic Acid Synthesis Inhibitors; D015638:Cytochalasin D; D010958:Plasminogen; D019061:src-Family Kinases; D014568:Urokinase-Type Plasminogen Activator; D017364:Collagenases; D018093:Gelatinases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9; D001839:Bombesin