A synthetic triterpenoid CDDO-Im inhibits tumorsphere formation by regulating stem cell signaling pathways in triple-negative breast cancer
Triple-negative breast cancer is associated with poor prognosis because of a high rate of tumor recurrence and metastasis. Previous studies demonstrated that the synthetic triterpenoid, CDDO-Imidazolide (CDDO-Im) induced cell cycle arrest and apoptosis in triple-negative breast cancer. Since a small...
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| description | Triple-negative breast cancer is associated with poor prognosis because of a high rate of tumor recurrence and metastasis. Previous studies demonstrated that the synthetic triterpenoid, CDDO-Imidazolide (CDDO-Im) induced cell cycle arrest and apoptosis in triple-negative breast cancer. Since a small subpopulation of cancer stem cells has been suggested to be responsible for drug resistance and metastasis of tumors, our present study determined whether the effects of CDDO-Im in triple-negative breast cancer are due to the inhibition of a cancer stem cell subpopulation. CDDO-Im treatment markedly induced cell cycle arrest at G2/M-phase and apoptosis in the triple-negative breast cancer cell lines, SUM159 and MDA-MB-231. Because SUM159 cells were more sensitive to CDDO-Im than MDA-MB-231 cells, the effects of CDDO-Im on the cancer stem cell subpopulation were further investigated in SUM159 cells. SUM159 cells formed tumorspheres in culture, and the cancer stem cell subpopulation, CD24-/EpCAM+ cells, was markedly enriched in SUM159 tumorspheres. The CD24-/EpCAM+ cells in SUM159 tumorspheres were significantly inhibited by CDDO-Im treatment. CDDO-Im also significantly decreased sphere forming efficiency and tumorsphere size in both primary and secondary sphere cultures. PCR array of stem cell signaling genes showed that expression levels of many key molecules in the stem cell signaling pathways, such as Notch, TGF-β/Smad, Hedgehog and Wnt, were significantly down-regulated by CDDO-Im in SUM159 tumorspheres. Protein levels of Notch receptors (c-Notch1, Notch1 and Notch3), TGF-β/Smad (pSmad2/3) and Hedgehog downstream effectors (GLI1) also were markedly reduced by CDDO-Im. In conclusion, the present study demonstrates that the synthetic triterpenoid, CDDO-Im, is a potent anti-cancer agent against triple-negative breast cancer cells by targeting the cancer stem cell subpopulation. |
| doi_str_mv | 10.1371/journal.pone.0107616 |
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Previous studies demonstrated that the synthetic triterpenoid, CDDO-Imidazolide (CDDO-Im) induced cell cycle arrest and apoptosis in triple-negative breast cancer. Since a small subpopulation of cancer stem cells has been suggested to be responsible for drug resistance and metastasis of tumors, our present study determined whether the effects of CDDO-Im in triple-negative breast cancer are due to the inhibition of a cancer stem cell subpopulation. CDDO-Im treatment markedly induced cell cycle arrest at G2/M-phase and apoptosis in the triple-negative breast cancer cell lines, SUM159 and MDA-MB-231. Because SUM159 cells were more sensitive to CDDO-Im than MDA-MB-231 cells, the effects of CDDO-Im on the cancer stem cell subpopulation were further investigated in SUM159 cells. SUM159 cells formed tumorspheres in culture, and the cancer stem cell subpopulation, CD24-/EpCAM+ cells, was markedly enriched in SUM159 tumorspheres. The CD24-/EpCAM+ cells in SUM159 tumorspheres were significantly inhibited by CDDO-Im treatment. CDDO-Im also significantly decreased sphere forming efficiency and tumorsphere size in both primary and secondary sphere cultures. PCR array of stem cell signaling genes showed that expression levels of many key molecules in the stem cell signaling pathways, such as Notch, TGF-β/Smad, Hedgehog and Wnt, were significantly down-regulated by CDDO-Im in SUM159 tumorspheres. Protein levels of Notch receptors (c-Notch1, Notch1 and Notch3), TGF-β/Smad (pSmad2/3) and Hedgehog downstream effectors (GLI1) also were markedly reduced by CDDO-Im. In conclusion, the present study demonstrates that the synthetic triterpenoid, CDDO-Im, is a potent anti-cancer agent against triple-negative breast cancer cells by targeting the cancer stem cell subpopulation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0107616</identifier><identifier>PMID: 25229616</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anticancer properties ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Biology ; Biology and Life Sciences ; Breast cancer ; Cancer ; Cell culture ; Cell cycle ; Cell Cycle Checkpoints - drug effects ; Cell growth ; Cell Line, Tumor ; Chemotherapy ; Deoxyribonucleic acid ; DNA ; DNA damage ; Dose-Response Relationship, Drug ; Drug resistance ; Experiments ; G2 Phase Cell Cycle Checkpoints - drug effects ; Gene expression ; Growth factors ; Hedgehog Proteins - metabolism ; Humans ; Imidazoles - pharmacology ; M Phase Cell Cycle Checkpoints - drug effects ; Medicine and Health Sciences ; Metastases ; Mutation ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - pathology ; Notch protein ; Notch1 protein ; Notch3 protein ; Oleanolic Acid - analogs & derivatives ; Oleanolic Acid - pharmacology ; Pathways ; Penicillin ; Pharmacy ; Receptors ; Receptors, Notch - metabolism ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Smad protein ; Stem cells ; Transforming Growth Factor beta - metabolism ; Triple Negative Breast Neoplasms - pathology ; Tumor cell lines ; Tumors ; Wnt protein</subject><ispartof>PloS one, 2014-09, Vol.9 (9), p.e107616</ispartof><rights>2014 So 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>2014 So et al 2014 So et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-4a0e557eb929d1c3994a1040f2e3f3af78c17407eb301d39935c9858091f1edc3</citedby><cites>FETCH-LOGICAL-c526t-4a0e557eb929d1c3994a1040f2e3f3af78c17407eb301d39935c9858091f1edc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167992/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167992/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25229616$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Samant, Rajeev</contributor><creatorcontrib>So, Jae Young</creatorcontrib><creatorcontrib>Lin, Janice J</creatorcontrib><creatorcontrib>Wahler, Joseph</creatorcontrib><creatorcontrib>Liby, Karen T</creatorcontrib><creatorcontrib>Sporn, Michael B</creatorcontrib><creatorcontrib>Suh, Nanjoo</creatorcontrib><title>A synthetic triterpenoid CDDO-Im inhibits tumorsphere formation by regulating stem cell signaling pathways in triple-negative breast cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Triple-negative breast cancer is associated with poor prognosis because of a high rate of tumor recurrence and metastasis. Previous studies demonstrated that the synthetic triterpenoid, CDDO-Imidazolide (CDDO-Im) induced cell cycle arrest and apoptosis in triple-negative breast cancer. Since a small subpopulation of cancer stem cells has been suggested to be responsible for drug resistance and metastasis of tumors, our present study determined whether the effects of CDDO-Im in triple-negative breast cancer are due to the inhibition of a cancer stem cell subpopulation. CDDO-Im treatment markedly induced cell cycle arrest at G2/M-phase and apoptosis in the triple-negative breast cancer cell lines, SUM159 and MDA-MB-231. Because SUM159 cells were more sensitive to CDDO-Im than MDA-MB-231 cells, the effects of CDDO-Im on the cancer stem cell subpopulation were further investigated in SUM159 cells. SUM159 cells formed tumorspheres in culture, and the cancer stem cell subpopulation, CD24-/EpCAM+ cells, was markedly enriched in SUM159 tumorspheres. The CD24-/EpCAM+ cells in SUM159 tumorspheres were significantly inhibited by CDDO-Im treatment. CDDO-Im also significantly decreased sphere forming efficiency and tumorsphere size in both primary and secondary sphere cultures. PCR array of stem cell signaling genes showed that expression levels of many key molecules in the stem cell signaling pathways, such as Notch, TGF-β/Smad, Hedgehog and Wnt, were significantly down-regulated by CDDO-Im in SUM159 tumorspheres. Protein levels of Notch receptors (c-Notch1, Notch1 and Notch3), TGF-β/Smad (pSmad2/3) and Hedgehog downstream effectors (GLI1) also were markedly reduced by CDDO-Im. In conclusion, the present study demonstrates that the synthetic triterpenoid, CDDO-Im, is a potent anti-cancer agent against triple-negative breast cancer cells by targeting the cancer stem cell subpopulation.</description><subject>Anticancer properties</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cell culture</subject><subject>Cell cycle</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug resistance</subject><subject>Experiments</subject><subject>G2 Phase Cell Cycle Checkpoints - drug effects</subject><subject>Gene expression</subject><subject>Growth factors</subject><subject>Hedgehog Proteins - metabolism</subject><subject>Humans</subject><subject>Imidazoles - pharmacology</subject><subject>M Phase Cell Cycle Checkpoints - drug effects</subject><subject>Medicine and Health Sciences</subject><subject>Metastases</subject><subject>Mutation</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Notch protein</subject><subject>Notch1 protein</subject><subject>Notch3 protein</subject><subject>Oleanolic Acid - analogs & derivatives</subject><subject>Oleanolic Acid - pharmacology</subject><subject>Pathways</subject><subject>Penicillin</subject><subject>Pharmacy</subject><subject>Receptors</subject><subject>Receptors, Notch - metabolism</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Smad protein</subject><subject>Stem cells</subject><subject>Transforming Growth Factor beta - metabolism</subject><subject>Triple Negative Breast Neoplasms - 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Previous studies demonstrated that the synthetic triterpenoid, CDDO-Imidazolide (CDDO-Im) induced cell cycle arrest and apoptosis in triple-negative breast cancer. Since a small subpopulation of cancer stem cells has been suggested to be responsible for drug resistance and metastasis of tumors, our present study determined whether the effects of CDDO-Im in triple-negative breast cancer are due to the inhibition of a cancer stem cell subpopulation. CDDO-Im treatment markedly induced cell cycle arrest at G2/M-phase and apoptosis in the triple-negative breast cancer cell lines, SUM159 and MDA-MB-231. Because SUM159 cells were more sensitive to CDDO-Im than MDA-MB-231 cells, the effects of CDDO-Im on the cancer stem cell subpopulation were further investigated in SUM159 cells. SUM159 cells formed tumorspheres in culture, and the cancer stem cell subpopulation, CD24-/EpCAM+ cells, was markedly enriched in SUM159 tumorspheres. The CD24-/EpCAM+ cells in SUM159 tumorspheres were significantly inhibited by CDDO-Im treatment. CDDO-Im also significantly decreased sphere forming efficiency and tumorsphere size in both primary and secondary sphere cultures. PCR array of stem cell signaling genes showed that expression levels of many key molecules in the stem cell signaling pathways, such as Notch, TGF-β/Smad, Hedgehog and Wnt, were significantly down-regulated by CDDO-Im in SUM159 tumorspheres. Protein levels of Notch receptors (c-Notch1, Notch1 and Notch3), TGF-β/Smad (pSmad2/3) and Hedgehog downstream effectors (GLI1) also were markedly reduced by CDDO-Im. In conclusion, the present study demonstrates that the synthetic triterpenoid, CDDO-Im, is a potent anti-cancer agent against triple-negative breast cancer cells by targeting the cancer stem cell subpopulation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25229616</pmid><doi>10.1371/journal.pone.0107616</doi><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Anticancer properties Antineoplastic Agents - pharmacology Apoptosis Apoptosis - drug effects Biology Biology and Life Sciences Breast cancer Cancer Cell culture Cell cycle Cell Cycle Checkpoints - drug effects Cell growth Cell Line, Tumor Chemotherapy Deoxyribonucleic acid DNA DNA damage Dose-Response Relationship, Drug Drug resistance Experiments G2 Phase Cell Cycle Checkpoints - drug effects Gene expression Growth factors Hedgehog Proteins - metabolism Humans Imidazoles - pharmacology M Phase Cell Cycle Checkpoints - drug effects Medicine and Health Sciences Metastases Mutation Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - pathology Notch protein Notch1 protein Notch3 protein Oleanolic Acid - analogs & derivatives Oleanolic Acid - pharmacology Pathways Penicillin Pharmacy Receptors Receptors, Notch - metabolism Signal transduction Signal Transduction - drug effects Signaling Smad protein Stem cells Transforming Growth Factor beta - metabolism Triple Negative Breast Neoplasms - pathology Tumor cell lines Tumors Wnt protein |
| title | A synthetic triterpenoid CDDO-Im inhibits tumorsphere formation by regulating stem cell signaling pathways in triple-negative breast cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-27T08%3A08%3A15IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20synthetic%20triterpenoid%20CDDO-Im%20inhibits%20tumorsphere%20formation%20by%20regulating%20stem%20cell%20signaling%20pathways%20in%20triple-negative%20breast%20cancer&rft.jtitle=PloS%20one&rft.au=So,%20Jae%20Young&rft.date=2014-09-17&rft.volume=9&rft.issue=9&rft.spage=e107616&rft.pages=e107616-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0107616&rft_dat=%3Cproquest_plos_%3E3435345881%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1562655736&rft_id=info:pmid/25229616&rft_doaj_id=oai_doaj_org_article_9112faeb1c7f460aa8e33b26a7002669&rfr_iscdi=true |