Original ContributionReduced nonprotein thiols inhibit activation and function of MMP-9: Implications for chemoprevention
Section snippets
Oral squamous cell carcinoma cell lines
Five cell lines derived from HNSCCs of the tongue that developed in men between the ages of 25 and 70 years were obtained from the American Type Culture Collection. All of the SCC cell lines are aneuploid, are immortalized, have an epithelial morphology, and show growth rates ranging between 0.8 and 1.0 population doublings/day. Our laboratory has confirmed that these SCC cell lines retain many characteristics of oral mucosa, inclusive of preservation of antioxidant, cytoprotective enzymes and
Reduced, nonprotein thiols inhibit APMA-induced activation of pro-MMP-9
Gelatin zymography results demonstrated that inclusion of either 2.5 mM GSH or 2.5 mM NAC inhibited APMA-induced activation of pro-MMP-9 (Fig. 1A). In contrast, addition of 2.5 mM GSSG did not affect APMA-induced activation of MMP-9 (Fig. 1A). Equimolar levels of either GSH or NAC did not affect APMA-mediated MMP-9 activation. Further, although GSH and NAC did reduce APMA activation of pro-MMP-2, the extent of inhibition was appreciably less than the inhibitory effects noted with MMP-9 (data
Discussion
The oxidative stress that ensues during sustained inflammation perturbs the local redox balance, thereby establishing conditions that favor MMP activation [10]. Notably, increased MMP activity can promote carcinogenesis by numerous mechanisms that include enabling migration and invasion of cancer cells, release of sequestered growth factors, and facilitating tumor-associated angiogenesis. This study investigated the effects of two reduced nonprotein thiols, i.e.; GSH and NAC, on the activation
Acknowledgments
These studies were supported by NIH RO1 CA95901 and R21 CA111210 (S. R. Mallery).
References (47)
- et al.
Mitochondrial redox control of matrix metalloproteinases
Free Radic. Biol. Med.
(2004) - et al.
Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutathionylation via disulfide S-oxide formation
J. Biol. Chem.
(2001) - et al.
SOD, oxidative stress and human pathologies: a brief history and a future direction
Biomed. Pharmacother.
(2005) - et al.
Potent mechanism-based inhibitors for matrix metalloproteinases
J. Biol. Chem.
(2005) - et al.
Endostatin inhibits human tongue carcinoma cell invasion and intravasation and blocks the activation of matrix metalloprotease-2, -9, and -13
J. Biol. Chem.
(2003) - et al.
Crystal structure of human MMP9 in complex with a reverse hydroxamate inhibitor
J. Mol. Biol.
(2002) - et al.
Structural characterization of the catalytic active site in the latent and active natural gelatinase B from human neutrophils
J. Biol. Chem.
(2000) - et al.
Angiogenesis: regulators and clinical applications
Biochem. Pharmacol.
(2001) - et al.
Bioelectrochemistry
(2004) - et al.
Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function and biochemistry
Circ. Res.
(2003)