MAPK (ERK2) kinase—a key target for NSAIDs-induced inhibition of gastric cancer cell proliferation and growth

• Published in: Life sciences (1973) 2001-11, Vol.69 (25), p.3045-3054
• Main Authors: Husain, S.S., Szabo, I.L., Pai, R., Soreghan, B., Jones, M.K., Tarnawski, A.S.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - enzymology; Adenocarcinoma - pathology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Division - drug effects; Cell proliferation; Cyclooxygenase Inhibitors - pharmacology; DNA - biosynthesis; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; ERK2; Gastric cancer; Humans; In Situ Nick-End Labeling; Indomethacin - pharmacology; MAPK; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Nitrobenzenes - pharmacology; ras Proteins - biosynthesis; Stomach Neoplasms - enzymology; Stomach Neoplasms - pathology; Sulfonamides - pharmacology; Thymidine - metabolism; Tumor Cells, Cultured - drug effects
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(01)01411-4

Limited clinical and experimental studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) may inhibit gastric cancer growth. However, the mechanisms involved are not completely understood and cannot be explained by COX-2 inhibition alone. MAPK signaling pathway is essential for cell proliferation, but the effect of NSAIDs on MAPK activity and phosphorylation in gastric cancer has never been studied. Since increased and unregulated cell proliferation and reduced cell apoptosis are important features of cancer growth, we studied whether NS-398, a selective COX-2 inhibitor and/or indomethacin (IND), a non-selective NSAID: 1) inhibit gastric cancer cell proliferation, 2) whether this inhibition is mediated via MAPK (ERK2), and 3) whether NSAIDs enhance apoptosis in gastric cancer cells. Human gastric epithelial cells (MKN28) derived from gastric tubular adenocarcinoma were cultured and treated with either vehicle, IND (0.25–0.5mM) or NS-398 (50–100μM) for 6, 16, 24 and 48h. Studies: 1) Cellular proliferation was determined by 3H-thymidine uptake. 2) MAPK activity was measured by incorporation of radiolabeled phosphate into myelin basic protein. 3) Apoptosis was evaluated using TUNEL assay. IND and NS-398 significantly inhibited the proliferation of MKN28 cells at 24h by 3.5 – 5 fold (p72% inhibition; all p