Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells

We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of human breast cancer cells in culture and in vivo in association with apoptosis induction. The present study builds on these observations and demonstr...

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Veröffentlicht in:Carcinogenesis (New York) 2010-11, Vol.31 (11), p.1991-1998
Hauptverfasser: Lee, Joomin, Hahm, Eun-Ryeong, Singh, Shivendra V.
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container_end_page 1998
container_issue 11
container_start_page 1991
container_title Carcinogenesis (New York)
container_volume 31
creator Lee, Joomin
Hahm, Eun-Ryeong
Singh, Shivendra V.
description We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of human breast cancer cells in culture and in vivo in association with apoptosis induction. The present study builds on these observations and demonstrates that WA inhibits constitutive as well as interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies including breast cancer. The WA treatment (2 and 4 μM) decreased constitutive (MDA-MB-231) and/or IL-6-inducible (MDA-MB-231 and MCF-7) phosphorylation of STAT3 (Tyr705) and its upstream regulator Janus-activated kinase 2 (JAK2; Tyr1007/1008) in MDA-MB-231, which was accompanied by suppression of their protein levels especially at the higher concentration. Exposure of MDA-MB-231 or MCF-7 cells to WA also resulted in suppression of (i) transcriptional activity of STAT3 with or without IL-6 stimulation in both cells; (ii) dimerization of STAT3 (MDA-MB-231) and (iii) nuclear translocation of Tyr705-phosphorylated STAT3 in both cells. To our surprise, the IL-6-stimulation, either before or after WA treatment, did not have an appreciable effect on WA-mediated apoptosis in MDA-MB-231 or MCF-7 cell line. The IL-6-stimulated activation of STAT3 conferred a modest protection against WA-mediated suppression of MDA-MB-231 cell invasion. General implication of these findings is that WA can trigger apoptosis and largely inhibit cell migration/invasion of breast cancer cells even after IL-6-induced activation of STAT3, which should be viewed as a therapeutic advantage for this agent.
doi_str_mv 10.1093/carcin/bgq175
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The present study builds on these observations and demonstrates that WA inhibits constitutive as well as interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies including breast cancer. The WA treatment (2 and 4 μM) decreased constitutive (MDA-MB-231) and/or IL-6-inducible (MDA-MB-231 and MCF-7) phosphorylation of STAT3 (Tyr705) and its upstream regulator Janus-activated kinase 2 (JAK2; Tyr1007/1008) in MDA-MB-231, which was accompanied by suppression of their protein levels especially at the higher concentration. Exposure of MDA-MB-231 or MCF-7 cells to WA also resulted in suppression of (i) transcriptional activity of STAT3 with or without IL-6 stimulation in both cells; (ii) dimerization of STAT3 (MDA-MB-231) and (iii) nuclear translocation of Tyr705-phosphorylated STAT3 in both cells. To our surprise, the IL-6-stimulation, either before or after WA treatment, did not have an appreciable effect on WA-mediated apoptosis in MDA-MB-231 or MCF-7 cell line. The IL-6-stimulated activation of STAT3 conferred a modest protection against WA-mediated suppression of MDA-MB-231 cell invasion. 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Obstetrics ; Humans ; Interleukin-6 - pharmacology ; Luciferases - metabolism ; Mammary gland diseases ; Medical sciences ; Phosphorylation - drug effects ; STAT3 Transcription Factor - antagonists &amp; inhibitors ; STAT3 Transcription Factor - metabolism ; Tumor Cells, Cultured ; Tumors ; Withanolides - pharmacology</subject><ispartof>Carcinogenesis (New York), 2010-11, Vol.31 (11), p.1991-1998</ispartof><rights>2015 INIST-CNRS</rights><rights>The Author 2010. Published by Oxford University Press. All rights reserved. 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To our surprise, the IL-6-stimulation, either before or after WA treatment, did not have an appreciable effect on WA-mediated apoptosis in MDA-MB-231 or MCF-7 cell line. The IL-6-stimulated activation of STAT3 conferred a modest protection against WA-mediated suppression of MDA-MB-231 cell invasion. 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Obstetrics</subject><subject>Humans</subject><subject>Interleukin-6 - pharmacology</subject><subject>Luciferases - metabolism</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Phosphorylation - drug effects</subject><subject>STAT3 Transcription Factor - antagonists &amp; inhibitors</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><subject>Withanolides - pharmacology</subject><issn>0143-3334</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkDtPwzAUhS0EgvIYWZEXxoAdx3ayICHES1RiAARisewbuzWkTrFTBP-elEILk4fznXOtD6F9So4oqdgx6Ag-HJvRG5V8DQ1oIUiW05KsowGhBcsYY8UW2k7phRAqGK820VZOZF4wyQYoPfpurJ2NPuBT7MPYG98lrKHz77rzbcCtw8mPgm5wF3VI9QxsxDrUv0wb58h3BtFPvzusX8Lj2UQHbKLVqcOgw7wHtmnSLtpwukl27-fdQQ8X5_dnV9nw9vL67HSYAc9JlzkhJZiqgpJxWVPIa2m4teBIbcvC0qriFmoJnLqyqAUYZwzNgZbCEGqgYjvoZLE7nZmJrcGG_peNmkY_0fFTtdqr_0nwYzVq31VeCcF50Q9kiwGIbUrRumWXEjW3rxb21cJ-zx_8Pbikf3X3wOEPoBPoxvXSwKcVx5gQrCxXh33q7Mcy1_FVCckkV1dPz-qeXtxwcvesKPsC-MGjIA</recordid><startdate>20101101</startdate><enddate>20101101</enddate><creator>Lee, Joomin</creator><creator>Hahm, Eun-Ryeong</creator><creator>Singh, Shivendra V.</creator><general>Oxford University Press</general><scope>BSCLL</scope><scope>IQODW</scope><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>5PM</scope></search><sort><creationdate>20101101</creationdate><title>Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells</title><author>Lee, Joomin ; Hahm, Eun-Ryeong ; Singh, Shivendra V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c520t-f677cb99c8357d1c2d7b5eecf0de84e1995ecd7c51f84d6cbfbb12c186b01bc93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Apoptosis - drug effects</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer Prevention</topic><topic>Carcinogenesis, carcinogens and anticarcinogens</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Movement - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Dimerization</topic><topic>Female</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Interleukin-6 - pharmacology</topic><topic>Luciferases - metabolism</topic><topic>Mammary gland diseases</topic><topic>Medical sciences</topic><topic>Phosphorylation - drug effects</topic><topic>STAT3 Transcription Factor - antagonists &amp; inhibitors</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><topic>Withanolides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Joomin</creatorcontrib><creatorcontrib>Hahm, Eun-Ryeong</creatorcontrib><creatorcontrib>Singh, Shivendra V.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Joomin</au><au>Hahm, Eun-Ryeong</au><au>Singh, Shivendra V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>2010-11-01</date><risdate>2010</risdate><volume>31</volume><issue>11</issue><spage>1991</spage><epage>1998</epage><pages>1991-1998</pages><issn>0143-3334</issn><eissn>1460-2180</eissn><coden>CRNGDP</coden><abstract>We have shown previously that withaferin A (WA), a promising anticancer constituent of Ayurvedic medicine plant Withania somnifera, inhibits growth of human breast cancer cells in culture and in vivo in association with apoptosis induction. The present study builds on these observations and demonstrates that WA inhibits constitutive as well as interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies including breast cancer. The WA treatment (2 and 4 μM) decreased constitutive (MDA-MB-231) and/or IL-6-inducible (MDA-MB-231 and MCF-7) phosphorylation of STAT3 (Tyr705) and its upstream regulator Janus-activated kinase 2 (JAK2; Tyr1007/1008) in MDA-MB-231, which was accompanied by suppression of their protein levels especially at the higher concentration. Exposure of MDA-MB-231 or MCF-7 cells to WA also resulted in suppression of (i) transcriptional activity of STAT3 with or without IL-6 stimulation in both cells; (ii) dimerization of STAT3 (MDA-MB-231) and (iii) nuclear translocation of Tyr705-phosphorylated STAT3 in both cells. To our surprise, the IL-6-stimulation, either before or after WA treatment, did not have an appreciable effect on WA-mediated apoptosis in MDA-MB-231 or MCF-7 cell line. The IL-6-stimulated activation of STAT3 conferred a modest protection against WA-mediated suppression of MDA-MB-231 cell invasion. General implication of these findings is that WA can trigger apoptosis and largely inhibit cell migration/invasion of breast cancer cells even after IL-6-induced activation of STAT3, which should be viewed as a therapeutic advantage for this agent.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>20724373</pmid><doi>10.1093/carcin/bgq175</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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subjects Apoptosis - drug effects
Biological and medical sciences
Blotting, Western
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer Prevention
Carcinogenesis, carcinogens and anticarcinogens
Cell Adhesion - drug effects
Cell Movement - drug effects
Cell Proliferation - drug effects
Dimerization
Female
Gynecology. Andrology. Obstetrics
Humans
Interleukin-6 - pharmacology
Luciferases - metabolism
Mammary gland diseases
Medical sciences
Phosphorylation - drug effects
STAT3 Transcription Factor - antagonists & inhibitors
STAT3 Transcription Factor - metabolism
Tumor Cells, Cultured
Tumors
Withanolides - pharmacology
title Withaferin A inhibits activation of signal transducer and activator of transcription 3 in human breast cancer cells
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