Coumestrol suppresses hypoxia inducible factor 1α by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells
Among many signals to regulate hypoxia inducible factor 1α (HIF-1α), sphingosine kinase 1 (SPHK1) is also involved in various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, molecular mechanisms of coumestrol were investiga...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-06, Vol.24 (11), p.2560-2564 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Cho, Sung-Yun Cho, Sunmi Park, Eunkyung Kim, Bonglee Sohn, Eun Jung Oh, Bumsuk Lee, Eun-Ok Lee, Hyo-Jeong Kim, Sung-Hoon |
| description | Among many signals to regulate hypoxia inducible factor 1α (HIF-1α), sphingosine kinase 1 (SPHK1) is also involved in various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, molecular mechanisms of coumestrol were investigated on the SPHK1 and HIF-1α signaling pathway in hypoxic PC-3 prostate cancer cells. Coumestrol significantly suppressed SPHK1 activity and accumulation of HIF-1α in a time- and concentration-dependent manner in hypoxic PC-3 cells. In addition, coumestrol inhibited the phosphorylation status of AKT and glycogen synthase kinase-3β (GSK 3β) signaling involved in cancer metabolism. Furthermore, SPHK1 siRNA transfection, sphigosine kinase inhibitor (SKI), reactive oxygen species (ROS) enhanced the inhibitory effect of coumestrol on the accumulation of HIF-1α and the expression of pAKT and pGSK 3β in hypoxic PC-3 cells by combination index. Overall, our findings suggest that coumestrol suppresses the accumulation of HIF-1α via suppression of SPHK1 pathway in hypoxic PC-3 cells. |
| doi_str_mv | 10.1016/j.bmcl.2014.03.084 |
| format | Article |
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Thus, in the present study, molecular mechanisms of coumestrol were investigated on the SPHK1 and HIF-1α signaling pathway in hypoxic PC-3 prostate cancer cells. Coumestrol significantly suppressed SPHK1 activity and accumulation of HIF-1α in a time- and concentration-dependent manner in hypoxic PC-3 cells. In addition, coumestrol inhibited the phosphorylation status of AKT and glycogen synthase kinase-3β (GSK 3β) signaling involved in cancer metabolism. Furthermore, SPHK1 siRNA transfection, sphigosine kinase inhibitor (SKI), reactive oxygen species (ROS) enhanced the inhibitory effect of coumestrol on the accumulation of HIF-1α and the expression of pAKT and pGSK 3β in hypoxic PC-3 cells by combination index. Overall, our findings suggest that coumestrol suppresses the accumulation of HIF-1α via suppression of SPHK1 pathway in hypoxic PC-3 cells.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2014.03.084</identifier><identifier>PMID: 24768446</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Cell Line, Tumor ; Coumestrol ; Coumestrol - chemistry ; Coumestrol - pharmacology ; Dose-Response Relationship, Drug ; Humans ; Hypoxia inducible factor 1α ; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors ; Molecular Structure ; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors ; Phosphotransferases (Alcohol Group Acceptor) - metabolism ; Reactive oxygen species ; Reactive Oxygen Species - antagonists & inhibitors ; Reactive Oxygen Species - metabolism ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2014-06, Vol.24 (11), p.2560-2564</ispartof><rights>2014</rights><rights>Copyright © 2014. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-dd53749d6f4a84220a430daaa314d3e6adec4c1b0a434da819f21aa7d32454fc3</citedby><cites>FETCH-LOGICAL-c389t-dd53749d6f4a84220a430daaa314d3e6adec4c1b0a434da819f21aa7d32454fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2014.03.084$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27911,27912,45982</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24768446$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cho, Sung-Yun</creatorcontrib><creatorcontrib>Cho, Sunmi</creatorcontrib><creatorcontrib>Park, Eunkyung</creatorcontrib><creatorcontrib>Kim, Bonglee</creatorcontrib><creatorcontrib>Sohn, Eun Jung</creatorcontrib><creatorcontrib>Oh, Bumsuk</creatorcontrib><creatorcontrib>Lee, Eun-Ok</creatorcontrib><creatorcontrib>Lee, Hyo-Jeong</creatorcontrib><creatorcontrib>Kim, Sung-Hoon</creatorcontrib><title>Coumestrol suppresses hypoxia inducible factor 1α by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Among many signals to regulate hypoxia inducible factor 1α (HIF-1α), sphingosine kinase 1 (SPHK1) is also involved in various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, molecular mechanisms of coumestrol were investigated on the SPHK1 and HIF-1α signaling pathway in hypoxic PC-3 prostate cancer cells. Coumestrol significantly suppressed SPHK1 activity and accumulation of HIF-1α in a time- and concentration-dependent manner in hypoxic PC-3 cells. In addition, coumestrol inhibited the phosphorylation status of AKT and glycogen synthase kinase-3β (GSK 3β) signaling involved in cancer metabolism. Furthermore, SPHK1 siRNA transfection, sphigosine kinase inhibitor (SKI), reactive oxygen species (ROS) enhanced the inhibitory effect of coumestrol on the accumulation of HIF-1α and the expression of pAKT and pGSK 3β in hypoxic PC-3 cells by combination index. Overall, our findings suggest that coumestrol suppresses the accumulation of HIF-1α via suppression of SPHK1 pathway in hypoxic PC-3 cells.</description><subject>Cell Line, Tumor</subject><subject>Coumestrol</subject><subject>Coumestrol - chemistry</subject><subject>Coumestrol - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Hypoxia inducible factor 1α</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors</subject><subject>Molecular Structure</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors</subject><subject>Phosphotransferases (Alcohol Group Acceptor) - metabolism</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - antagonists & inhibitors</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxi1ERZfCC_SAfOSS1I4n2UTqpVrRglSpVQGJmzWxJ10v-YedIPYN-jq8CM-Eo91y5DTSp998mvk-xs6lSKWQxcUurTvTppmQkAqVihJesJWEAhIFIn_JVqIqRFJW8O2UvQ5hJyIoAF6x0wzWRQlQrNjTZpg7CpMfWh7mcfQUAgW-3Y_DL4fc9XY2rm6JN2imwXP55zev91HfutpNrn_kD3efeUfW4USWh3EbtSG4nvh312MgLiN89DP8fpMoPvohTBHnBntDnhtq2_CGnTTYBnp7nGfs6_WHL5uPye3dzafN1W1iVFlNibW5WkNliwawhCwTCEpYRFQSrKICLRkwsl50sFjKqskk4tqqDHJojDpj7w--8Yofc_xcdy4sF2BPwxy0zBWUolznMqLZATXx4OCp0aN3Hfq9lkIvDeidXhrQSwNaKB0biEvvjv5zHWP5t_IceQQuDwDFL3868joYRzEI6zyZSdvB_c__LyJEmlw</recordid><startdate>20140601</startdate><enddate>20140601</enddate><creator>Cho, Sung-Yun</creator><creator>Cho, Sunmi</creator><creator>Park, Eunkyung</creator><creator>Kim, Bonglee</creator><creator>Sohn, Eun Jung</creator><creator>Oh, Bumsuk</creator><creator>Lee, Eun-Ok</creator><creator>Lee, Hyo-Jeong</creator><creator>Kim, Sung-Hoon</creator><general>Elsevier Ltd</general><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20140601</creationdate><title>Coumestrol suppresses hypoxia inducible factor 1α by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells</title><author>Cho, Sung-Yun ; Cho, Sunmi ; Park, Eunkyung ; Kim, Bonglee ; Sohn, Eun Jung ; Oh, Bumsuk ; Lee, Eun-Ok ; Lee, Hyo-Jeong ; Kim, Sung-Hoon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-dd53749d6f4a84220a430daaa314d3e6adec4c1b0a434da819f21aa7d32454fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Cell Line, Tumor</topic><topic>Coumestrol</topic><topic>Coumestrol - chemistry</topic><topic>Coumestrol - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Hypoxia inducible factor 1α</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors</topic><topic>Molecular Structure</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors</topic><topic>Phosphotransferases (Alcohol Group Acceptor) - metabolism</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - antagonists & inhibitors</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cho, Sung-Yun</creatorcontrib><creatorcontrib>Cho, Sunmi</creatorcontrib><creatorcontrib>Park, Eunkyung</creatorcontrib><creatorcontrib>Kim, Bonglee</creatorcontrib><creatorcontrib>Sohn, Eun Jung</creatorcontrib><creatorcontrib>Oh, Bumsuk</creatorcontrib><creatorcontrib>Lee, Eun-Ok</creatorcontrib><creatorcontrib>Lee, Hyo-Jeong</creatorcontrib><creatorcontrib>Kim, Sung-Hoon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cho, Sung-Yun</au><au>Cho, Sunmi</au><au>Park, Eunkyung</au><au>Kim, Bonglee</au><au>Sohn, Eun Jung</au><au>Oh, Bumsuk</au><au>Lee, Eun-Ok</au><au>Lee, Hyo-Jeong</au><au>Kim, Sung-Hoon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Coumestrol suppresses hypoxia inducible factor 1α by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2014-06-01</date><risdate>2014</risdate><volume>24</volume><issue>11</issue><spage>2560</spage><epage>2564</epage><pages>2560-2564</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>Among many signals to regulate hypoxia inducible factor 1α (HIF-1α), sphingosine kinase 1 (SPHK1) is also involved in various biological activities such as cell growth, survival, invasion, angiogenesis, and carcinogenesis. Thus, in the present study, molecular mechanisms of coumestrol were investigated on the SPHK1 and HIF-1α signaling pathway in hypoxic PC-3 prostate cancer cells. Coumestrol significantly suppressed SPHK1 activity and accumulation of HIF-1α in a time- and concentration-dependent manner in hypoxic PC-3 cells. In addition, coumestrol inhibited the phosphorylation status of AKT and glycogen synthase kinase-3β (GSK 3β) signaling involved in cancer metabolism. Furthermore, SPHK1 siRNA transfection, sphigosine kinase inhibitor (SKI), reactive oxygen species (ROS) enhanced the inhibitory effect of coumestrol on the accumulation of HIF-1α and the expression of pAKT and pGSK 3β in hypoxic PC-3 cells by combination index. 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| ispartof | Bioorganic & medicinal chemistry letters, 2014-06, Vol.24 (11), p.2560-2564 |
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| subjects | Cell Line, Tumor Coumestrol Coumestrol - chemistry Coumestrol - pharmacology Dose-Response Relationship, Drug Humans Hypoxia inducible factor 1α Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors Molecular Structure Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors Phosphotransferases (Alcohol Group Acceptor) - metabolism Reactive oxygen species Reactive Oxygen Species - antagonists & inhibitors Reactive Oxygen Species - metabolism Structure-Activity Relationship |
| title | Coumestrol suppresses hypoxia inducible factor 1α by inhibiting ROS mediated sphingosine kinase 1 in hypoxic PC-3 prostate cancer cells |
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