Doxycycline down-regulates matrix metalloproteinase expression and inhibits NF-κB signaling in LPS-induced PC3 cells

Abstract

Introduction. Matrix metalloproteinase enzymes (MMPs) play important role in inflammation, malignant cell proliferation, invasion and angiogenesis by mediating extracellular matrix degradation. Doxycycline, a synthetic tetracycline, behaves as a MMP inhibitor at a subantimicrobial dose and inhibits tumor cell proliferation, invasion and angiogenesis. The aberrant activity of nuclear factor kappa B (NF-kB) causes activation of MMPs and thereby proliferation and invasion of cancer cells. The aim of this study was to investigate the effects of doxycycline on the expression of MMPs in lipopolysaccharide (LPS)-induced PC3 human prostate cancer cells and the possible role of NF-kB signaling. Material and methods. PC3 cells were incubated with LPS (0.5 µg/mL) for 24 h in the presence or absence of doxycycline (5 µg/mL). The effects of LPS and doxycycline on the expressions of MMP-2, MMP-8, MMP-9, MMP-10, NF-kB/p65, IkB-a, p-IkB-a, IKK-b were examined by Western blotting and immunohistochemistry in PC3 cells. Furthermore, relative proteinase activities of MMP-2 and MMP-9 were determined by gelatin zymography. Results. LPS increased expression and activity of MMP-9 and expression of MMP-8, MMP-10, NF-kB/p65, p-IkB-a, IKK-b and doxycycline down-regulated its effects with the exception of MMP-10 expression. The expression of MMP-2 and IkB-a was affected by neither LPS nor doxycycline. Conclusions. Our findings indicate that doxycycline inhibits the expression of various MMPs and NF-kB signaling may play a role in the regulation of MMPs expression in LPS-induced PC3 human prostate cancer cells.

<p>Low-dose doxycycline inhibits hydrogen peroxide-induced oxidative stress, MMP-2 up-regulation and contractile dysfunction in human saphenous vein grafts</p>

“…The intensity of immunopositivity for each MMP protein in intima, media and adventitia layers was evaluated semi-quantitatively using immunoscoring scale. Immunoscoring was performed by assessing the intensity of positive cytoplasmic staining of cells and by scoring according to the following scale: negative (0), weak (1), moderate (2) and strong (3) immunoreactivity. 28 A mean score was calculated for each sample.…”

Neurotrophic keratopathy

“…Matrix metalloproteinases inhibitors (oral tetracyclines and topical acetylcysteine) restrict neutrophil collagenase and epithelial gelatinase gene expression, suppress alpha-1 antitrypsin degradation and scavenge reactive oxygen species (Ogut et al, 2016;Hahn et al, 2016;Abdul-Hussien et al, 2009;Sekundo et al, 2002). Ascorbate applied topically or given systemically, provides cofactors for collagen synthesis as well as scavenging for oxygen free radicals.…”

Diabetic Corneal Neuropathy

“…In the event of corneal infection, stromal degradation and melting can occur, due to the release of proteolytic enzymes from the recruited inflammatory cells, as well as the activation of pro-inflammatory and tissue-destructive cascades. Topical and/or systemic administration of tetracyclines, macrolides, acetylcysteine or ascorbate has been used to prevent corneal melting because they inhibit matrix metalloproteinases (MMPs) and collagen degradation, downregulate neutrophil collagenase expression, suppress neutrophil degranulation and scavenge ROS [118][119][120].…”