Loading…
MAPK (ERK2) kinase—a key target for NSAIDs-induced inhibition of gastric cancer cell proliferation and growth
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 prol...
Saved in:
| Published in: | Life sciences (1973) 2001-11, Vol.69 (25), p.3045-3054 |
|---|---|
| Main Authors: | , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c361t-ada19e73118cd968679b6a7b0965d8d713c74f6eb5c9c35fa86173a0ebac62b43 |
|---|---|
| cites | |
| container_end_page | 3054 |
| container_issue | 25 |
| container_start_page | 3045 |
| container_title | Life sciences (1973) |
| container_volume | 69 |
| creator | Husain, S.S. Szabo, I.L. Pai, R. Soreghan, B. Jones, M.K. Tarnawski, A.S. |
| description | 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 |
| doi_str_mv | 10.1016/S0024-3205(01)01411-4 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_72332885</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0024320501014114</els_id><sourcerecordid>72332885</sourcerecordid><originalsourceid>FETCH-LOGICAL-c361t-ada19e73118cd968679b6a7b0965d8d713c74f6eb5c9c35fa86173a0ebac62b43</originalsourceid><addsrcrecordid>eNqFkMtuEzEUhi1ERULhEUBeoWQxrc94fJkVikppq7aAKKwtj30mMU3GrT0BdcdD9Al5kk4ugiWrs_nO-f_zEfIG2BEwkMc3jJVVwUsmJgymDCqAonpGxqBVXTDJ4TkZ_0VG5GXOPxhjQij-gowAlNCaszGJ17Mvl3Ry-vWynNLb0NmMf34_WnqLD7S3aY49bWOin25mFx9yETq_duhp6BahCX2IHY0tndvcp-Cos53DRB0ul_QuxWVoMdktZDtP5yn-6hevyEFrlxlf7-ch-f7x9NvJeXH1-eziZHZVOC6hL6y3UKPiANr5Wmqp6kZa1bBaCq-9Au5U1UpshKsdF63VEhS3DBvrZNlU_JC8290dityvMfdmFfKmme0wrrNRJeel1mIAxQ50KeacsDV3KaxsejDAzMa02Zo2G42GgdmaNpuAt_uAdbNC_29rr3YA3u8AHN78GTCZ7AIOhnxI6HrjY_hPxBNnG43J</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>72332885</pqid></control><display><type>article</type><title>MAPK (ERK2) kinase—a key target for NSAIDs-induced inhibition of gastric cancer cell proliferation and growth</title><source>ScienceDirect Freedom Collection 2022-2024</source><creator>Husain, S.S. ; Szabo, I.L. ; Pai, R. ; Soreghan, B. ; Jones, M.K. ; Tarnawski, A.S.</creator><creatorcontrib>Husain, S.S. ; Szabo, I.L. ; Pai, R. ; Soreghan, B. ; Jones, M.K. ; Tarnawski, A.S.</creatorcontrib><description>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 (p<0.002) and at 48h by 2.5 – 10 fold (p<0.02). Both NSAIDs also significantly inhibited ERK2 activity: IND >53% inhibition, NS-398, 100μM >72% inhibition; all p<0.05. Both IND and NS-398 significantly increased apoptotic index. In conclusion, IND and NS-398 significantly inhibit proliferation and growth of human gastric cancer cell line MKN28. This effect is mediated by NSAID-induced inhibition of MAPK (ERK2) kinase signaling pathway, essential for cell proliferation. NSAIDs also increase apoptosis in MKN28 cells. In addition to inhibiting cyclooxygenase, NSAIDs inhibit phosphorylating enzymes - kinases essential for signaling cell proliferation.</description><identifier>ISSN: 0024-3205</identifier><identifier>EISSN: 1879-0631</identifier><identifier>DOI: 10.1016/S0024-3205(01)01411-4</identifier><identifier>PMID: 11758830</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>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</subject><ispartof>Life sciences (1973), 2001-11, Vol.69 (25), p.3045-3054</ispartof><rights>2001 Elsevier Science Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c361t-ada19e73118cd968679b6a7b0965d8d713c74f6eb5c9c35fa86173a0ebac62b43</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11758830$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Husain, S.S.</creatorcontrib><creatorcontrib>Szabo, I.L.</creatorcontrib><creatorcontrib>Pai, R.</creatorcontrib><creatorcontrib>Soreghan, B.</creatorcontrib><creatorcontrib>Jones, M.K.</creatorcontrib><creatorcontrib>Tarnawski, A.S.</creatorcontrib><title>MAPK (ERK2) kinase—a key target for NSAIDs-induced inhibition of gastric cancer cell proliferation and growth</title><title>Life sciences (1973)</title><addtitle>Life Sci</addtitle><description>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 (p<0.002) and at 48h by 2.5 – 10 fold (p<0.02). Both NSAIDs also significantly inhibited ERK2 activity: IND >53% inhibition, NS-398, 100μM >72% inhibition; all p<0.05. Both IND and NS-398 significantly increased apoptotic index. In conclusion, IND and NS-398 significantly inhibit proliferation and growth of human gastric cancer cell line MKN28. This effect is mediated by NSAID-induced inhibition of MAPK (ERK2) kinase signaling pathway, essential for cell proliferation. NSAIDs also increase apoptosis in MKN28 cells. In addition to inhibiting cyclooxygenase, NSAIDs inhibit phosphorylating enzymes - kinases essential for signaling cell proliferation.</description><subject>Adenocarcinoma - enzymology</subject><subject>Adenocarcinoma - pathology</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Cell Division - drug effects</subject><subject>Cell proliferation</subject><subject>Cyclooxygenase Inhibitors - pharmacology</subject><subject>DNA - biosynthesis</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>ERK2</subject><subject>Gastric cancer</subject><subject>Humans</subject><subject>In Situ Nick-End Labeling</subject><subject>Indomethacin - pharmacology</subject><subject>MAPK</subject><subject>Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Nitrobenzenes - pharmacology</subject><subject>ras Proteins - biosynthesis</subject><subject>Stomach Neoplasms - enzymology</subject><subject>Stomach Neoplasms - pathology</subject><subject>Sulfonamides - pharmacology</subject><subject>Thymidine - metabolism</subject><subject>Tumor Cells, Cultured - drug effects</subject><issn>0024-3205</issn><issn>1879-0631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><recordid>eNqFkMtuEzEUhi1ERULhEUBeoWQxrc94fJkVikppq7aAKKwtj30mMU3GrT0BdcdD9Al5kk4ugiWrs_nO-f_zEfIG2BEwkMc3jJVVwUsmJgymDCqAonpGxqBVXTDJ4TkZ_0VG5GXOPxhjQij-gowAlNCaszGJ17Mvl3Ry-vWynNLb0NmMf34_WnqLD7S3aY49bWOin25mFx9yETq_duhp6BahCX2IHY0tndvcp-Cos53DRB0ul_QuxWVoMdktZDtP5yn-6hevyEFrlxlf7-ch-f7x9NvJeXH1-eziZHZVOC6hL6y3UKPiANr5Wmqp6kZa1bBaCq-9Au5U1UpshKsdF63VEhS3DBvrZNlU_JC8290dityvMfdmFfKmme0wrrNRJeel1mIAxQ50KeacsDV3KaxsejDAzMa02Zo2G42GgdmaNpuAt_uAdbNC_29rr3YA3u8AHN78GTCZ7AIOhnxI6HrjY_hPxBNnG43J</recordid><startdate>20011109</startdate><enddate>20011109</enddate><creator>Husain, S.S.</creator><creator>Szabo, I.L.</creator><creator>Pai, R.</creator><creator>Soreghan, B.</creator><creator>Jones, M.K.</creator><creator>Tarnawski, A.S.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20011109</creationdate><title>MAPK (ERK2) kinase—a key target for NSAIDs-induced inhibition of gastric cancer cell proliferation and growth</title><author>Husain, S.S. ; Szabo, I.L. ; Pai, R. ; Soreghan, B. ; Jones, M.K. ; Tarnawski, A.S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c361t-ada19e73118cd968679b6a7b0965d8d713c74f6eb5c9c35fa86173a0ebac62b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adenocarcinoma - enzymology</topic><topic>Adenocarcinoma - pathology</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Cell Division - drug effects</topic><topic>Cell proliferation</topic><topic>Cyclooxygenase Inhibitors - pharmacology</topic><topic>DNA - biosynthesis</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Screening Assays, Antitumor</topic><topic>ERK2</topic><topic>Gastric cancer</topic><topic>Humans</topic><topic>In Situ Nick-End Labeling</topic><topic>Indomethacin - pharmacology</topic><topic>MAPK</topic><topic>Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Nitrobenzenes - pharmacology</topic><topic>ras Proteins - biosynthesis</topic><topic>Stomach Neoplasms - enzymology</topic><topic>Stomach Neoplasms - pathology</topic><topic>Sulfonamides - pharmacology</topic><topic>Thymidine - metabolism</topic><topic>Tumor Cells, Cultured - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Husain, S.S.</creatorcontrib><creatorcontrib>Szabo, I.L.</creatorcontrib><creatorcontrib>Pai, R.</creatorcontrib><creatorcontrib>Soreghan, B.</creatorcontrib><creatorcontrib>Jones, M.K.</creatorcontrib><creatorcontrib>Tarnawski, A.S.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Life sciences (1973)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Husain, S.S.</au><au>Szabo, I.L.</au><au>Pai, R.</au><au>Soreghan, B.</au><au>Jones, M.K.</au><au>Tarnawski, A.S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MAPK (ERK2) kinase—a key target for NSAIDs-induced inhibition of gastric cancer cell proliferation and growth</atitle><jtitle>Life sciences (1973)</jtitle><addtitle>Life Sci</addtitle><date>2001-11-09</date><risdate>2001</risdate><volume>69</volume><issue>25</issue><spage>3045</spage><epage>3054</epage><pages>3045-3054</pages><issn>0024-3205</issn><eissn>1879-0631</eissn><abstract>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 (p<0.002) and at 48h by 2.5 – 10 fold (p<0.02). Both NSAIDs also significantly inhibited ERK2 activity: IND >53% inhibition, NS-398, 100μM >72% inhibition; all p<0.05. Both IND and NS-398 significantly increased apoptotic index. In conclusion, IND and NS-398 significantly inhibit proliferation and growth of human gastric cancer cell line MKN28. This effect is mediated by NSAID-induced inhibition of MAPK (ERK2) kinase signaling pathway, essential for cell proliferation. NSAIDs also increase apoptosis in MKN28 cells. In addition to inhibiting cyclooxygenase, NSAIDs inhibit phosphorylating enzymes - kinases essential for signaling cell proliferation.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>11758830</pmid><doi>10.1016/S0024-3205(01)01411-4</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0024-3205 |
| ispartof | Life sciences (1973), 2001-11, Vol.69 (25), p.3045-3054 |
| issn | 0024-3205 1879-0631 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_72332885 |
| source | ScienceDirect Freedom Collection 2022-2024 |
| 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 |
| title | MAPK (ERK2) kinase—a key target for NSAIDs-induced inhibition of gastric cancer cell proliferation and growth |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-06T23%3A38%3A21IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MAPK%20(ERK2)%20kinase%E2%80%94a%20key%20target%20for%20NSAIDs-induced%20inhibition%20of%20gastric%20cancer%20cell%20proliferation%20and%20growth&rft.jtitle=Life%20sciences%20(1973)&rft.au=Husain,%20S.S.&rft.date=2001-11-09&rft.volume=69&rft.issue=25&rft.spage=3045&rft.epage=3054&rft.pages=3045-3054&rft.issn=0024-3205&rft.eissn=1879-0631&rft_id=info:doi/10.1016/S0024-3205(01)01411-4&rft_dat=%3Cproquest_cross%3E72332885%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c361t-ada19e73118cd968679b6a7b0965d8d713c74f6eb5c9c35fa86173a0ebac62b43%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=72332885&rft_id=info:pmid/11758830&rfr_iscdi=true |