Anti-metastatic effect of metformin via repression of interleukin 6-induced epithelial-mesenchymal transition in human colon cancer cells
Metformin, a first-line drug used to treat type 2 diabetes, has also been shown to have anticancer effects against a variety of malignancies, including colorectal cancer. Although inhibition of the mTOR pathway is known to be the most important mechanism for the antitumor effects of metformin, other...
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| creator | Kang, Sanghee Kim, Bo Ram Kang, Myoung-Hee Kim, Dae-Young Lee, Dae-Hee Oh, Sang Cheul Min, Byung Wook Um, Jun Won |
| description | Metformin, a first-line drug used to treat type 2 diabetes, has also been shown to have anticancer effects against a variety of malignancies, including colorectal cancer. Although inhibition of the mTOR pathway is known to be the most important mechanism for the antitumor effects of metformin, other mechanisms remain unclear. The purpose of this study was to identify the antitumor mechanism of metformin in colorectal cancer using high-throughput data, and then test the mechanism experimentally. We identified the gene signature of metformin-treated colon cancer cells. This signature was processed for prediction using colon adenocarcinoma patient data from the Cancer Genome Atlas to classify the patients showing a gene expression pattern similar to that in metformin-treated cells. This patient group showed better overall and disease-free survival. Furthermore, pathway analysis revealed that the metformin-predicted group was characterized by decreased interleukin (IL)-6 pathway signaling, epithelial-mesenchymal transition, and colon cancer metastatic signaling. We induced epithelial-mesenchymal transition in colon cancer cell lines via IL-6 treatment, which increased cell motility and promoted invasion. However, these effects were blocked by metformin. These findings suggest that blockade of IL-6-induced epithelial-mesenchymal transition is an antitumor mechanism of metformin. |
| doi_str_mv | 10.1371/journal.pone.0205449 |
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Although inhibition of the mTOR pathway is known to be the most important mechanism for the antitumor effects of metformin, other mechanisms remain unclear. The purpose of this study was to identify the antitumor mechanism of metformin in colorectal cancer using high-throughput data, and then test the mechanism experimentally. We identified the gene signature of metformin-treated colon cancer cells. This signature was processed for prediction using colon adenocarcinoma patient data from the Cancer Genome Atlas to classify the patients showing a gene expression pattern similar to that in metformin-treated cells. This patient group showed better overall and disease-free survival. Furthermore, pathway analysis revealed that the metformin-predicted group was characterized by decreased interleukin (IL)-6 pathway signaling, epithelial-mesenchymal transition, and colon cancer metastatic signaling. We induced epithelial-mesenchymal transition in colon cancer cell lines via IL-6 treatment, which increased cell motility and promoted invasion. However, these effects were blocked by metformin. These findings suggest that blockade of IL-6-induced epithelial-mesenchymal transition is an antitumor mechanism of metformin.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0205449</identifier><identifier>PMID: 30308035</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenocarcinoma ; Angiogenesis ; Anticancer properties ; Antidiabetics ; Antitumor activity ; Biology and Life Sciences ; Breast cancer ; Cancer ; Cell cycle ; Cell growth ; Cell survival ; Chemotherapy ; Colon ; Colon cancer ; Colorectal cancer ; Colorectal carcinoma ; Cytokines ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Gene expression ; Genomes ; Growth factors ; Hospitals ; Insulin resistance ; Interleukin 6 ; Kinases ; Medicine ; Medicine and Health Sciences ; Mesenchyme ; Metastases ; Metastasis ; Metformin ; Mortality ; Oncology ; Patients ; Predictions ; Prostate ; Proteins ; Signal transduction ; Signaling ; Surgery ; Survival analysis ; TOR protein ; Tumor cell lines ; Tumorigenesis</subject><ispartof>PloS one, 2018-10, Vol.13 (10), p.e0205449-e0205449</ispartof><rights>2018 Kang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Kang et al 2018 Kang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-2a3bde204fc14dcc6b734d25bba83e9442e7c8616cabe706a767e17593123b7d3</citedby><cites>FETCH-LOGICAL-c526t-2a3bde204fc14dcc6b734d25bba83e9442e7c8616cabe706a767e17593123b7d3</cites><orcidid>0000-0002-6097-8831</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181375/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6181375/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30308035$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Castresana, Javier S.</contributor><creatorcontrib>Kang, Sanghee</creatorcontrib><creatorcontrib>Kim, Bo Ram</creatorcontrib><creatorcontrib>Kang, Myoung-Hee</creatorcontrib><creatorcontrib>Kim, Dae-Young</creatorcontrib><creatorcontrib>Lee, Dae-Hee</creatorcontrib><creatorcontrib>Oh, Sang Cheul</creatorcontrib><creatorcontrib>Min, Byung Wook</creatorcontrib><creatorcontrib>Um, Jun Won</creatorcontrib><title>Anti-metastatic effect of metformin via repression of interleukin 6-induced epithelial-mesenchymal transition in human colon cancer cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Metformin, a first-line drug used to treat type 2 diabetes, has also been shown to have anticancer effects against a variety of malignancies, including colorectal cancer. Although inhibition of the mTOR pathway is known to be the most important mechanism for the antitumor effects of metformin, other mechanisms remain unclear. The purpose of this study was to identify the antitumor mechanism of metformin in colorectal cancer using high-throughput data, and then test the mechanism experimentally. We identified the gene signature of metformin-treated colon cancer cells. This signature was processed for prediction using colon adenocarcinoma patient data from the Cancer Genome Atlas to classify the patients showing a gene expression pattern similar to that in metformin-treated cells. This patient group showed better overall and disease-free survival. Furthermore, pathway analysis revealed that the metformin-predicted group was characterized by decreased interleukin (IL)-6 pathway signaling, epithelial-mesenchymal transition, and colon cancer metastatic signaling. We induced epithelial-mesenchymal transition in colon cancer cell lines via IL-6 treatment, which increased cell motility and promoted invasion. However, these effects were blocked by metformin. These findings suggest that blockade of IL-6-induced epithelial-mesenchymal transition is an antitumor mechanism of metformin.</description><subject>Adenocarcinoma</subject><subject>Angiogenesis</subject><subject>Anticancer properties</subject><subject>Antidiabetics</subject><subject>Antitumor activity</subject><subject>Biology and Life Sciences</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell survival</subject><subject>Chemotherapy</subject><subject>Colon</subject><subject>Colon cancer</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Cytokines</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Gene expression</subject><subject>Genomes</subject><subject>Growth factors</subject><subject>Hospitals</subject><subject>Insulin resistance</subject><subject>Interleukin 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effect of metformin via repression of interleukin 6-induced epithelial-mesenchymal transition in human colon cancer cells</title><author>Kang, Sanghee ; Kim, Bo Ram ; Kang, Myoung-Hee ; Kim, Dae-Young ; Lee, Dae-Hee ; Oh, Sang Cheul ; Min, Byung Wook ; Um, Jun Won</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-2a3bde204fc14dcc6b734d25bba83e9442e7c8616cabe706a767e17593123b7d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adenocarcinoma</topic><topic>Angiogenesis</topic><topic>Anticancer properties</topic><topic>Antidiabetics</topic><topic>Antitumor activity</topic><topic>Biology and Life Sciences</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell survival</topic><topic>Chemotherapy</topic><topic>Colon</topic><topic>Colon cancer</topic><topic>Colorectal cancer</topic><topic>Colorectal 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| subjects | Adenocarcinoma Angiogenesis Anticancer properties Antidiabetics Antitumor activity Biology and Life Sciences Breast cancer Cancer Cell cycle Cell growth Cell survival Chemotherapy Colon Colon cancer Colorectal cancer Colorectal carcinoma Cytokines Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Gene expression Genomes Growth factors Hospitals Insulin resistance Interleukin 6 Kinases Medicine Medicine and Health Sciences Mesenchyme Metastases Metastasis Metformin Mortality Oncology Patients Predictions Prostate Proteins Signal transduction Signaling Surgery Survival analysis TOR protein Tumor cell lines Tumorigenesis |
| title | Anti-metastatic effect of metformin via repression of interleukin 6-induced epithelial-mesenchymal transition in human colon cancer cells |
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