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Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4
BACKGROUND: Increasing evidence indicates that the interaction between the CXC chemokine receptor-4 (CXCR4) and its ligand CXCL12 is critical in the process of metastasis that accounts for more than 90% of cancer-related deaths. Thus, novel agents that can downregulate the CXCR4/CXCL12 axis have the...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175200/ https://www.ncbi.nlm.nih.gov/pubmed/21880153 http://dx.doi.org/10.1186/1476-4598-10-107 |
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author | Manu, Kanjoormana Aryan Shanmugam, Muthu K Rajendran, Peramaiyan Li, Feng Ramachandran, Lalitha Hay, Hui Sin Kannaiyan, Radhamani Swamy, Shivananju Nanjunda Vali, Shireen Kapoor, Shweta Ramesh, Bhargavi Bist, Pradeep Koay, Evelyn S Lim, Lina HK Ahn, Kwang Seok Kumar, Alan Prem Sethi, Gautam |
author_facet | Manu, Kanjoormana Aryan Shanmugam, Muthu K Rajendran, Peramaiyan Li, Feng Ramachandran, Lalitha Hay, Hui Sin Kannaiyan, Radhamani Swamy, Shivananju Nanjunda Vali, Shireen Kapoor, Shweta Ramesh, Bhargavi Bist, Pradeep Koay, Evelyn S Lim, Lina HK Ahn, Kwang Seok Kumar, Alan Prem Sethi, Gautam |
author_sort | Manu, Kanjoormana Aryan |
collection | PubMed |
description | BACKGROUND: Increasing evidence indicates that the interaction between the CXC chemokine receptor-4 (CXCR4) and its ligand CXCL12 is critical in the process of metastasis that accounts for more than 90% of cancer-related deaths. Thus, novel agents that can downregulate the CXCR4/CXCL12 axis have therapeutic potential in inhibiting cancer metastasis. METHODS: In this report, we investigated the potential of an agent, plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), for its ability to modulate CXCR4 expression and function in various tumor cells using Western blot analysis, DNA binding assay, transient transfection, real time PCR analysis, chromatin immunoprecipitation, and cellular migration and invasion assays. RESULTS: We found that plumbagin downregulated the expression of CXCR4 in breast cancer cells irrespective of their HER2 status. The decrease in CXCR4 expression induced by plumbagin was not cell type-specific as the inhibition also occurred in gastric, lung, renal, oral, and hepatocellular tumor cell lines. Neither proteasome inhibition nor lysosomal stabilization had any effect on plumbagin-induced decrease in CXCR4 expression. Detailed study of the underlying molecular mechanism(s) revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, inhibition of NF-κB activation, and suppression of chromatin immunoprecipitation activity. In addition, using a virtual, predictive, functional proteomics-based tumor pathway platform, we tested the hypothesis that NF-κB inhibition by plumbagin causes the decrease in CXCR4 and other metastatic genes. Suppression of CXCR4 expression by plumbagin was found to correlate with the inhibition of CXCL12-induced migration and invasion of both breast and gastric cancer cells. CONCLUSIONS: Overall, our results indicate, for the first time, that plumbagin is a novel blocker of CXCR4 expression and thus has the potential to suppress metastasis of cancer. |
format | Online Article Text |
id | pubmed-3175200 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-31752002011-09-18 Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4 Manu, Kanjoormana Aryan Shanmugam, Muthu K Rajendran, Peramaiyan Li, Feng Ramachandran, Lalitha Hay, Hui Sin Kannaiyan, Radhamani Swamy, Shivananju Nanjunda Vali, Shireen Kapoor, Shweta Ramesh, Bhargavi Bist, Pradeep Koay, Evelyn S Lim, Lina HK Ahn, Kwang Seok Kumar, Alan Prem Sethi, Gautam Mol Cancer Research BACKGROUND: Increasing evidence indicates that the interaction between the CXC chemokine receptor-4 (CXCR4) and its ligand CXCL12 is critical in the process of metastasis that accounts for more than 90% of cancer-related deaths. Thus, novel agents that can downregulate the CXCR4/CXCL12 axis have therapeutic potential in inhibiting cancer metastasis. METHODS: In this report, we investigated the potential of an agent, plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), for its ability to modulate CXCR4 expression and function in various tumor cells using Western blot analysis, DNA binding assay, transient transfection, real time PCR analysis, chromatin immunoprecipitation, and cellular migration and invasion assays. RESULTS: We found that plumbagin downregulated the expression of CXCR4 in breast cancer cells irrespective of their HER2 status. The decrease in CXCR4 expression induced by plumbagin was not cell type-specific as the inhibition also occurred in gastric, lung, renal, oral, and hepatocellular tumor cell lines. Neither proteasome inhibition nor lysosomal stabilization had any effect on plumbagin-induced decrease in CXCR4 expression. Detailed study of the underlying molecular mechanism(s) revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, inhibition of NF-κB activation, and suppression of chromatin immunoprecipitation activity. In addition, using a virtual, predictive, functional proteomics-based tumor pathway platform, we tested the hypothesis that NF-κB inhibition by plumbagin causes the decrease in CXCR4 and other metastatic genes. Suppression of CXCR4 expression by plumbagin was found to correlate with the inhibition of CXCL12-induced migration and invasion of both breast and gastric cancer cells. CONCLUSIONS: Overall, our results indicate, for the first time, that plumbagin is a novel blocker of CXCR4 expression and thus has the potential to suppress metastasis of cancer. BioMed Central 2011-09-01 /pmc/articles/PMC3175200/ /pubmed/21880153 http://dx.doi.org/10.1186/1476-4598-10-107 Text en Copyright ©2011 Manu et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Manu, Kanjoormana Aryan Shanmugam, Muthu K Rajendran, Peramaiyan Li, Feng Ramachandran, Lalitha Hay, Hui Sin Kannaiyan, Radhamani Swamy, Shivananju Nanjunda Vali, Shireen Kapoor, Shweta Ramesh, Bhargavi Bist, Pradeep Koay, Evelyn S Lim, Lina HK Ahn, Kwang Seok Kumar, Alan Prem Sethi, Gautam Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4 |
title | Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4 |
title_full | Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4 |
title_fullStr | Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4 |
title_full_unstemmed | Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4 |
title_short | Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4 |
title_sort | plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor cxcr4 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175200/ https://www.ncbi.nlm.nih.gov/pubmed/21880153 http://dx.doi.org/10.1186/1476-4598-10-107 |
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