Cytokine-suppressive anti-inflammatory drugs (CSAIDs) inhibit invasion and MMP-1 production of ovarian carcinoma cells.
The development of therapeutic strategies for inhibition of peritoneal dissemination and invasion would be central for the treatment of ovarian carcinoma. In the microenvironment of ovarian carcinomas, various inflammatory cytokines like tumor necrosis factor alpha (TNF-alpha) are present. In this study we investigated the role of inflammatory cytokines in the regulation of invasion of SKOV-3 ovarian carcinoma cells in-vitro. Treatment of cells with TNF-alpha or interleukin 1beta (IL-1beta) lead to increased phosphorylation of the stress-activated p38 mitogen-activated protein kinase (p38MAPK). Furthermore, TNF-alpha as well as IL-1beta stimulated matrigel invasion of tumor cells. An inhibitor of stress-activated protein kinase pathways, the cytokine-suppressive anti-inflammatory drug (CSAID) SB203580 inhibited invasion of cytokine-stimulated SKOV-3 cells. The MEK-1 inhibitor PD98059 similarly inhibited invasion of cytokine-stimulated cells, but to a lesser extent. Expression of mRNA and protein levels of matrix metalloproteinase-1 (MMP-1) by SKOV-3 cells could be stimulated by inflammatory cytokines and inhibited by SB203580, and partially also by PD98059. Our results show that CSAIDs reduce invasion and MMP expression of ovarian carcinoma cells. Further studies are required to investigate whether inhibition of cytokine-induced signal transduction may be of value in therapy of ovarian carcinomas in-vivo.
Denkert
Carsten
C
Institute of Pathology, Charité Hospital, Campus Mitte, Schumannstr. 20/21, D-10117 Berlin, Germany.
Koch
Ines
I
Berger
Stefan
S
Köbel
Martin
M
Siegert
Antje
A
Hauptmann
Steffen
S
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003094:Collagen; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004338:Drug Combinations; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation; D007375:Interleukin-1 / Q000494:pharmacology; D007797:Laminin; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011509:Proteoglycans; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007375:Interleukin-1; D007797:Laminin; D009363:Neoplasm Proteins; D011509:Proteoglycans; D011725:Pyridines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; C059485:matrigel; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one