Salinomycin Suppresses LRP6 Expression and Inhibits Both Wnt/β-catenin and mTORC1 Signaling in Breast and Prostate Cancer Cells
Emerging evidence indicates that activation of Wnt/β‐catenin signaling at the cell surface results in inhibition of glycogen synthase kinase 3β (GSK3β), leading to activation of mTORC1 signaling in cancer cells. The low density lipoprotein receptor‐related protein‐6 (LRP6) is an essential Wnt co‐rec...
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| Veröffentlicht in: | Journal of cellular biochemistry 2014-10, Vol.115 (10), p.1799-1807 |
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| description | Emerging evidence indicates that activation of Wnt/β‐catenin signaling at the cell surface results in inhibition of glycogen synthase kinase 3β (GSK3β), leading to activation of mTORC1 signaling in cancer cells. The low density lipoprotein receptor‐related protein‐6 (LRP6) is an essential Wnt co‐receptor for Wnt/β‐catenin signaling. Salinomycin is a novel small molecule inhibitor of LRP6. In the present study, we found that LRP6 overexpression induced mTORC1 signaling activation in cancer cells, and that salinomycin was not only a potent Wnt/β‐catenin signaling inhibitor, but also a strong mTORC1 signaling antagonist in breast and prostate cancer cells. Mechanistically, salinomycin activated GSK3β in cancer cells. Moreover, salinomycin was able to suppress the expression of cyclin D1 and survivin, two targets of both Wnt/β‐catenin and mTORC1 signaling, in prostate and breast cancer cells, and displayed remarkable anticancer activity. Our results present novel mechanisms underlying salinomycin‐mediated cancer cell death. J. Cell. Biochem. 115: 1799–1807, 2014. © 2014 Wiley Periodicals, Inc. |
| doi_str_mv | 10.1002/jcb.24850 |
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The low density lipoprotein receptor‐related protein‐6 (LRP6) is an essential Wnt co‐receptor for Wnt/β‐catenin signaling. Salinomycin is a novel small molecule inhibitor of LRP6. In the present study, we found that LRP6 overexpression induced mTORC1 signaling activation in cancer cells, and that salinomycin was not only a potent Wnt/β‐catenin signaling inhibitor, but also a strong mTORC1 signaling antagonist in breast and prostate cancer cells. Mechanistically, salinomycin activated GSK3β in cancer cells. Moreover, salinomycin was able to suppress the expression of cyclin D1 and survivin, two targets of both Wnt/β‐catenin and mTORC1 signaling, in prostate and breast cancer cells, and displayed remarkable anticancer activity. Our results present novel mechanisms underlying salinomycin‐mediated cancer cell death. J. Cell. Biochem. 115: 1799–1807, 2014. © 2014 Wiley Periodicals, Inc.</description><identifier>ISSN: 0730-2312</identifier><identifier>EISSN: 1097-4644</identifier><identifier>DOI: 10.1002/jcb.24850</identifier><identifier>PMID: 24905570</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Anti-Bacterial Agents - pharmacology ; Apoptosis - drug effects ; beta Catenin - antagonists & inhibitors ; beta Catenin - metabolism ; Breast - metabolism ; Breast - pathology ; Breast Neoplasms - drug therapy ; CANCER ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival - drug effects ; Cyclin D1 - biosynthesis ; Enzyme Activation ; Female ; Glycogen Synthase Kinase 3 - metabolism ; Glycogen Synthase Kinase 3 beta ; HEK293 Cells ; Humans ; Inhibitor of Apoptosis Proteins - biosynthesis ; Low Density Lipoprotein Receptor-Related Protein-6 - biosynthesis ; LRP6 ; Male ; MCF-7 Cells ; Mechanistic Target of Rapamycin Complex 1 ; mTORC1 SIGNALING ; Multiprotein Complexes - antagonists & inhibitors ; Multiprotein Complexes - metabolism ; Prostate - metabolism ; Prostate - pathology ; Prostatic Neoplasms - drug therapy ; Pyrans - pharmacology ; SALINOMYCIN ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; TOR Serine-Threonine Kinases - metabolism ; Wnt Proteins - antagonists & inhibitors ; Wnt Proteins - metabolism ; Wnt SIGNALING ; Wnt Signaling Pathway - drug effects</subject><ispartof>Journal of cellular biochemistry, 2014-10, Vol.115 (10), p.1799-1807</ispartof><rights>2014 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4530-36243901e00c38e87eacef2ae8b728b704c7c099883d04b01d048e680697b52f3</citedby><cites>FETCH-LOGICAL-c4530-36243901e00c38e87eacef2ae8b728b704c7c099883d04b01d048e680697b52f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjcb.24850$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcb.24850$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,315,781,785,886,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24905570$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Wenyan</creatorcontrib><creatorcontrib>Li, Yonghe</creatorcontrib><title>Salinomycin Suppresses LRP6 Expression and Inhibits Both Wnt/β-catenin and mTORC1 Signaling in Breast and Prostate Cancer Cells</title><title>Journal of cellular biochemistry</title><addtitle>J. Cell. Biochem</addtitle><description>Emerging evidence indicates that activation of Wnt/β‐catenin signaling at the cell surface results in inhibition of glycogen synthase kinase 3β (GSK3β), leading to activation of mTORC1 signaling in cancer cells. The low density lipoprotein receptor‐related protein‐6 (LRP6) is an essential Wnt co‐receptor for Wnt/β‐catenin signaling. Salinomycin is a novel small molecule inhibitor of LRP6. In the present study, we found that LRP6 overexpression induced mTORC1 signaling activation in cancer cells, and that salinomycin was not only a potent Wnt/β‐catenin signaling inhibitor, but also a strong mTORC1 signaling antagonist in breast and prostate cancer cells. Mechanistically, salinomycin activated GSK3β in cancer cells. Moreover, salinomycin was able to suppress the expression of cyclin D1 and survivin, two targets of both Wnt/β‐catenin and mTORC1 signaling, in prostate and breast cancer cells, and displayed remarkable anticancer activity. Our results present novel mechanisms underlying salinomycin‐mediated cancer cell death. J. Cell. Biochem. 115: 1799–1807, 2014. © 2014 Wiley Periodicals, Inc.</description><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>beta Catenin - antagonists & inhibitors</subject><subject>beta Catenin - metabolism</subject><subject>Breast - metabolism</subject><subject>Breast - pathology</subject><subject>Breast Neoplasms - drug therapy</subject><subject>CANCER</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cell Survival - drug effects</subject><subject>Cyclin D1 - biosynthesis</subject><subject>Enzyme Activation</subject><subject>Female</subject><subject>Glycogen Synthase Kinase 3 - metabolism</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Inhibitor of Apoptosis Proteins - biosynthesis</subject><subject>Low Density Lipoprotein Receptor-Related Protein-6 - biosynthesis</subject><subject>LRP6</subject><subject>Male</subject><subject>MCF-7 Cells</subject><subject>Mechanistic Target of Rapamycin Complex 1</subject><subject>mTORC1 SIGNALING</subject><subject>Multiprotein Complexes - antagonists & inhibitors</subject><subject>Multiprotein Complexes - metabolism</subject><subject>Prostate - metabolism</subject><subject>Prostate - pathology</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Pyrans - pharmacology</subject><subject>SALINOMYCIN</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Wnt Proteins - antagonists & inhibitors</subject><subject>Wnt Proteins - metabolism</subject><subject>Wnt SIGNALING</subject><subject>Wnt Signaling Pathway - drug effects</subject><issn>0730-2312</issn><issn>1097-4644</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1uEzEUhS0EoiGw4AWQl3QxzfXPjGc2SGRUSquIRklRUTeWx3ESlxlPsCfQ7HgmHoRnws20ESxY-Fr2_e6xjw5CrwmcEAA6utXVCeV5Ck_QgEAhEp5x_hQNQDBIKCP0CL0I4RYAioLR5-iI8gLSVMAA_Zyr2rq22Wnr8Hy72XgTggl4Mptm-PRuf7Stw8ot8Llb28p2AY_bbo2vXTf6_SvRqjPO9kBzdTkrCZ7blbtXXeF4P_ZGhW7fnvo2dBHHpXLaeFyaug4v0bOlqoN59bAP0ecPp1flx2RyeXZevp8kmqfRBcsoZwUQA6BZbnJhlDZLqkxeCRoXcC10tJfnbAG8AhJrbrIcskJUKV2yIXrX6262VWMW2rjOq1puvG2U38lWWflvx9m1XLXfJSeMi1iG6O2DgG-_bU3oZGODjhaUM-02SJKmTEBasCKixz2qo-PgzfLwDAF5n5iMicl9YpF98_e_DuRjRBEY9cAPW5vd_5XkRTl-lEz6CRs6c3eYUP6rzAQTqbz-dCbz2c0XcXEzk1P2BzMzsF0</recordid><startdate>201410</startdate><enddate>201410</enddate><creator>Lu, Wenyan</creator><creator>Li, Yonghe</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>201410</creationdate><title>Salinomycin Suppresses LRP6 Expression and Inhibits Both Wnt/β-catenin and mTORC1 Signaling in Breast and Prostate Cancer Cells</title><author>Lu, Wenyan ; Li, Yonghe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4530-36243901e00c38e87eacef2ae8b728b704c7c099883d04b01d048e680697b52f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>beta Catenin - antagonists & inhibitors</topic><topic>beta Catenin - metabolism</topic><topic>Breast - metabolism</topic><topic>Breast - pathology</topic><topic>Breast Neoplasms - drug therapy</topic><topic>CANCER</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cell Survival - drug effects</topic><topic>Cyclin D1 - biosynthesis</topic><topic>Enzyme Activation</topic><topic>Female</topic><topic>Glycogen Synthase Kinase 3 - metabolism</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Inhibitor of Apoptosis Proteins - biosynthesis</topic><topic>Low Density Lipoprotein Receptor-Related Protein-6 - biosynthesis</topic><topic>LRP6</topic><topic>Male</topic><topic>MCF-7 Cells</topic><topic>Mechanistic Target of Rapamycin Complex 1</topic><topic>mTORC1 SIGNALING</topic><topic>Multiprotein Complexes - antagonists & inhibitors</topic><topic>Multiprotein Complexes - metabolism</topic><topic>Prostate - metabolism</topic><topic>Prostate - pathology</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Pyrans - pharmacology</topic><topic>SALINOMYCIN</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Wnt Proteins - antagonists & inhibitors</topic><topic>Wnt Proteins - metabolism</topic><topic>Wnt SIGNALING</topic><topic>Wnt Signaling Pathway - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lu, Wenyan</creatorcontrib><creatorcontrib>Li, Yonghe</creatorcontrib><collection>Istex</collection><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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lu, Wenyan</au><au>Li, Yonghe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Salinomycin Suppresses LRP6 Expression and Inhibits Both Wnt/β-catenin and mTORC1 Signaling in Breast and Prostate Cancer Cells</atitle><jtitle>Journal of cellular biochemistry</jtitle><addtitle>J. Cell. Biochem</addtitle><date>2014-10</date><risdate>2014</risdate><volume>115</volume><issue>10</issue><spage>1799</spage><epage>1807</epage><pages>1799-1807</pages><issn>0730-2312</issn><eissn>1097-4644</eissn><abstract>Emerging evidence indicates that activation of Wnt/β‐catenin signaling at the cell surface results in inhibition of glycogen synthase kinase 3β (GSK3β), leading to activation of mTORC1 signaling in cancer cells. The low density lipoprotein receptor‐related protein‐6 (LRP6) is an essential Wnt co‐receptor for Wnt/β‐catenin signaling. Salinomycin is a novel small molecule inhibitor of LRP6. In the present study, we found that LRP6 overexpression induced mTORC1 signaling activation in cancer cells, and that salinomycin was not only a potent Wnt/β‐catenin signaling inhibitor, but also a strong mTORC1 signaling antagonist in breast and prostate cancer cells. Mechanistically, salinomycin activated GSK3β in cancer cells. Moreover, salinomycin was able to suppress the expression of cyclin D1 and survivin, two targets of both Wnt/β‐catenin and mTORC1 signaling, in prostate and breast cancer cells, and displayed remarkable anticancer activity. Our results present novel mechanisms underlying salinomycin‐mediated cancer cell death. J. Cell. Biochem. 115: 1799–1807, 2014. © 2014 Wiley Periodicals, Inc.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>24905570</pmid><doi>10.1002/jcb.24850</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Anti-Bacterial Agents - pharmacology Apoptosis - drug effects beta Catenin - antagonists & inhibitors beta Catenin - metabolism Breast - metabolism Breast - pathology Breast Neoplasms - drug therapy CANCER Cell Line, Tumor Cell Proliferation Cell Survival - drug effects Cyclin D1 - biosynthesis Enzyme Activation Female Glycogen Synthase Kinase 3 - metabolism Glycogen Synthase Kinase 3 beta HEK293 Cells Humans Inhibitor of Apoptosis Proteins - biosynthesis Low Density Lipoprotein Receptor-Related Protein-6 - biosynthesis LRP6 Male MCF-7 Cells Mechanistic Target of Rapamycin Complex 1 mTORC1 SIGNALING Multiprotein Complexes - antagonists & inhibitors Multiprotein Complexes - metabolism Prostate - metabolism Prostate - pathology Prostatic Neoplasms - drug therapy Pyrans - pharmacology SALINOMYCIN TOR Serine-Threonine Kinases - antagonists & inhibitors TOR Serine-Threonine Kinases - metabolism Wnt Proteins - antagonists & inhibitors Wnt Proteins - metabolism Wnt SIGNALING Wnt Signaling Pathway - drug effects |
| title | Salinomycin Suppresses LRP6 Expression and Inhibits Both Wnt/β-catenin and mTORC1 Signaling in Breast and Prostate Cancer Cells |
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