Androgen Receptor Stimulates Hexokinase 2 and Induces Glycolysis by PKA/CREB Signaling in Hepatocellular Carcinoma
Background Hepatocellular carcinoma (HCC) escapes growth inhibition by upregulating hexokinase 2 (HK2); however, the mechanism by which tumor cells upregulate HK2 remains unclear. Aim We aimed to investigate the role of androgen receptor (AR) signalling in promoting HK2 expression in HCC. Methods Th...
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| Veröffentlicht in: | Digestive diseases and sciences 2021-03, Vol.66 (3), p.802-813 |
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| creator | Sun, R. F. Zhao, C. Y. Chen, S. Yu, W. Zhou, M. M. Gao, C. R. |
| description | Background
Hepatocellular carcinoma (HCC) escapes growth inhibition by upregulating hexokinase 2 (HK2); however, the mechanism by which tumor cells upregulate HK2 remains unclear.
Aim
We aimed to investigate the role of androgen receptor (AR) signalling in promoting HK2 expression in HCC.
Methods
The expressions of AR and HK2 in HCC tissues were analyzed by immunohistochemistry. Cell proliferation was determined using the CCK-8 assay, and the molecular mechanism of AR in the regulation of HK2 was evaluated by immunoblotting and luciferase assays.
Results
AR expression is positively correlated with HK2 staining by an immunohistochemical analysis. The manipulation of AR expression changed HK2 expression and glycolysis. AR signaling promoted the growth of HCC by enhancing HK2-mediated glycolysis. Moreover, AR stimulated HK2 levels and glycolysis by potentiating protein kinase A/cyclic adenosine monophosphate response element-binding (CREB) protein signaling. CREB silencing decreased HK2 expression and inhibited AR-mediated HCC glycolysis. AR affected the sensitivity of HCC cells to glycolysis inhibitors by regulating downstream phosphorylated (p)-CREB.
Conclusions
These results indicate that AR at least partially induced glycolysis via p-CREB regulation of HK2 in HCC cells. Thus, this pathway should be considered for the design of novel therapeutic methods to target AR-overexpressing HCC. |
| doi_str_mv | 10.1007/s10620-020-06229-y |
| format | Article |
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Hepatocellular carcinoma (HCC) escapes growth inhibition by upregulating hexokinase 2 (HK2); however, the mechanism by which tumor cells upregulate HK2 remains unclear.
Aim
We aimed to investigate the role of androgen receptor (AR) signalling in promoting HK2 expression in HCC.
Methods
The expressions of AR and HK2 in HCC tissues were analyzed by immunohistochemistry. Cell proliferation was determined using the CCK-8 assay, and the molecular mechanism of AR in the regulation of HK2 was evaluated by immunoblotting and luciferase assays.
Results
AR expression is positively correlated with HK2 staining by an immunohistochemical analysis. The manipulation of AR expression changed HK2 expression and glycolysis. AR signaling promoted the growth of HCC by enhancing HK2-mediated glycolysis. Moreover, AR stimulated HK2 levels and glycolysis by potentiating protein kinase A/cyclic adenosine monophosphate response element-binding (CREB) protein signaling. CREB silencing decreased HK2 expression and inhibited AR-mediated HCC glycolysis. AR affected the sensitivity of HCC cells to glycolysis inhibitors by regulating downstream phosphorylated (p)-CREB.
Conclusions
These results indicate that AR at least partially induced glycolysis via p-CREB regulation of HK2 in HCC cells. Thus, this pathway should be considered for the design of novel therapeutic methods to target AR-overexpressing HCC.</description><identifier>ISSN: 0163-2116</identifier><identifier>EISSN: 1573-2568</identifier><identifier>DOI: 10.1007/s10620-020-06229-y</identifier><identifier>PMID: 32274668</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Adenylic acid ; Analysis ; Androgens ; Anemia ; Binding sites ; Biochemistry ; Cancer ; Carcinoma ; Committees ; Gastroenterology ; Glucose ; Glucose metabolism ; Hepatology ; Immunohistochemistry ; Kinases ; Liver cancer ; Medicine ; Medicine & Public Health ; Metabolism ; Oncology ; Original Article ; Phenols ; Prostate cancer ; Protein binding ; Protein kinases ; Proteins ; Transcription factors ; Transplant Surgery</subject><ispartof>Digestive diseases and sciences, 2021-03, Vol.66 (3), p.802-813</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2020</rights><rights>COPYRIGHT 2021 Springer</rights><rights>Springer Science+Business Media, LLC, part of Springer Nature 2020.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c486t-8d6b88c3bbeb5b0f9ae15652d4d24dd884d9a817236f6e0c2d8645fa2058efe63</citedby><cites>FETCH-LOGICAL-c486t-8d6b88c3bbeb5b0f9ae15652d4d24dd884d9a817236f6e0c2d8645fa2058efe63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10620-020-06229-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10620-020-06229-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32274668$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, R. F.</creatorcontrib><creatorcontrib>Zhao, C. Y.</creatorcontrib><creatorcontrib>Chen, S.</creatorcontrib><creatorcontrib>Yu, W.</creatorcontrib><creatorcontrib>Zhou, M. M.</creatorcontrib><creatorcontrib>Gao, C. R.</creatorcontrib><title>Androgen Receptor Stimulates Hexokinase 2 and Induces Glycolysis by PKA/CREB Signaling in Hepatocellular Carcinoma</title><title>Digestive diseases and sciences</title><addtitle>Dig Dis Sci</addtitle><addtitle>Dig Dis Sci</addtitle><description>Background
Hepatocellular carcinoma (HCC) escapes growth inhibition by upregulating hexokinase 2 (HK2); however, the mechanism by which tumor cells upregulate HK2 remains unclear.
Aim
We aimed to investigate the role of androgen receptor (AR) signalling in promoting HK2 expression in HCC.
Methods
The expressions of AR and HK2 in HCC tissues were analyzed by immunohistochemistry. Cell proliferation was determined using the CCK-8 assay, and the molecular mechanism of AR in the regulation of HK2 was evaluated by immunoblotting and luciferase assays.
Results
AR expression is positively correlated with HK2 staining by an immunohistochemical analysis. The manipulation of AR expression changed HK2 expression and glycolysis. AR signaling promoted the growth of HCC by enhancing HK2-mediated glycolysis. Moreover, AR stimulated HK2 levels and glycolysis by potentiating protein kinase A/cyclic adenosine monophosphate response element-binding (CREB) protein signaling. CREB silencing decreased HK2 expression and inhibited AR-mediated HCC glycolysis. AR affected the sensitivity of HCC cells to glycolysis inhibitors by regulating downstream phosphorylated (p)-CREB.
Conclusions
These results indicate that AR at least partially induced glycolysis via p-CREB regulation of HK2 in HCC cells. Thus, this pathway should be considered for the design of novel therapeutic methods to target AR-overexpressing HCC.</description><subject>Adenylic acid</subject><subject>Analysis</subject><subject>Androgens</subject><subject>Anemia</subject><subject>Binding sites</subject><subject>Biochemistry</subject><subject>Cancer</subject><subject>Carcinoma</subject><subject>Committees</subject><subject>Gastroenterology</subject><subject>Glucose</subject><subject>Glucose metabolism</subject><subject>Hepatology</subject><subject>Immunohistochemistry</subject><subject>Kinases</subject><subject>Liver cancer</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolism</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Phenols</subject><subject>Prostate cancer</subject><subject>Protein binding</subject><subject>Protein kinases</subject><subject>Proteins</subject><subject>Transcription factors</subject><subject>Transplant Surgery</subject><issn>0163-2116</issn><issn>1573-2568</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kV9r1TAYxoMo7rj5BbyQgDfedMufNk0vj4e5DQeOTa9DmrwtmW1yTFqw396UMx2OIeElIfk9T96XB6F3lJxSQuqzRIlgpCBrCcaaYnmBNrSqecEqIV-iDaEinykVR-hNSveEkKam4jU64ozVpRByg-LW2xh68PgWDOynEPHd5MZ50BMkfAm_wg_ndQLMsPYWX3k7m_xwMSwmDEtyCbcLvvmyPdvdnn_Cd673enC-x85n8V5PwcAwZLeIdzoa58OoT9CrTg8J3j7sx-j75_Nvu8vi-uvF1W57XZhSiqmQVrRSGt620FYt6RoNtBIVs6VlpbVSlrbRktaMi04AMcxKUVadZqSS0IHgx-jjwXcfw88Z0qRGl9Z2tIcwJ8W4lJKRpqwz-uEJeh_mmEfJVNnUvK44ax6pXg-gnO_CFLVZTdW2phngolq_PX2GysvC6Ezw0Ll8_4-AHQQmhpQidGof3ajjoihRa9DqELQia61BqyWL3j90PLcj2L-SP8lmgB-AlJ98D_FxpP_Y_gbtALI1</recordid><startdate>20210301</startdate><enddate>20210301</enddate><creator>Sun, R. F.</creator><creator>Zhao, C. Y.</creator><creator>Chen, S.</creator><creator>Yu, W.</creator><creator>Zhou, M. M.</creator><creator>Gao, C. R.</creator><general>Springer US</general><general>Springer</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20210301</creationdate><title>Androgen Receptor Stimulates Hexokinase 2 and Induces Glycolysis by PKA/CREB Signaling in Hepatocellular Carcinoma</title><author>Sun, R. F. ; Zhao, C. Y. ; Chen, S. ; Yu, W. ; Zhou, M. M. ; Gao, C. R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c486t-8d6b88c3bbeb5b0f9ae15652d4d24dd884d9a817236f6e0c2d8645fa2058efe63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenylic acid</topic><topic>Analysis</topic><topic>Androgens</topic><topic>Anemia</topic><topic>Binding sites</topic><topic>Biochemistry</topic><topic>Cancer</topic><topic>Carcinoma</topic><topic>Committees</topic><topic>Gastroenterology</topic><topic>Glucose</topic><topic>Glucose metabolism</topic><topic>Hepatology</topic><topic>Immunohistochemistry</topic><topic>Kinases</topic><topic>Liver cancer</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolism</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Phenols</topic><topic>Prostate cancer</topic><topic>Protein binding</topic><topic>Protein kinases</topic><topic>Proteins</topic><topic>Transcription factors</topic><topic>Transplant Surgery</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, R. F.</creatorcontrib><creatorcontrib>Zhao, C. Y.</creatorcontrib><creatorcontrib>Chen, S.</creatorcontrib><creatorcontrib>Yu, W.</creatorcontrib><creatorcontrib>Zhou, M. M.</creatorcontrib><creatorcontrib>Gao, C. R.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Digestive diseases and sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, R. F.</au><au>Zhao, C. Y.</au><au>Chen, S.</au><au>Yu, W.</au><au>Zhou, M. M.</au><au>Gao, C. R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Androgen Receptor Stimulates Hexokinase 2 and Induces Glycolysis by PKA/CREB Signaling in Hepatocellular Carcinoma</atitle><jtitle>Digestive diseases and sciences</jtitle><stitle>Dig Dis Sci</stitle><addtitle>Dig Dis Sci</addtitle><date>2021-03-01</date><risdate>2021</risdate><volume>66</volume><issue>3</issue><spage>802</spage><epage>813</epage><pages>802-813</pages><issn>0163-2116</issn><eissn>1573-2568</eissn><abstract>Background
Hepatocellular carcinoma (HCC) escapes growth inhibition by upregulating hexokinase 2 (HK2); however, the mechanism by which tumor cells upregulate HK2 remains unclear.
Aim
We aimed to investigate the role of androgen receptor (AR) signalling in promoting HK2 expression in HCC.
Methods
The expressions of AR and HK2 in HCC tissues were analyzed by immunohistochemistry. Cell proliferation was determined using the CCK-8 assay, and the molecular mechanism of AR in the regulation of HK2 was evaluated by immunoblotting and luciferase assays.
Results
AR expression is positively correlated with HK2 staining by an immunohistochemical analysis. The manipulation of AR expression changed HK2 expression and glycolysis. AR signaling promoted the growth of HCC by enhancing HK2-mediated glycolysis. Moreover, AR stimulated HK2 levels and glycolysis by potentiating protein kinase A/cyclic adenosine monophosphate response element-binding (CREB) protein signaling. CREB silencing decreased HK2 expression and inhibited AR-mediated HCC glycolysis. AR affected the sensitivity of HCC cells to glycolysis inhibitors by regulating downstream phosphorylated (p)-CREB.
Conclusions
These results indicate that AR at least partially induced glycolysis via p-CREB regulation of HK2 in HCC cells. Thus, this pathway should be considered for the design of novel therapeutic methods to target AR-overexpressing HCC.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>32274668</pmid><doi>10.1007/s10620-020-06229-y</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenylic acid Analysis Androgens Anemia Binding sites Biochemistry Cancer Carcinoma Committees Gastroenterology Glucose Glucose metabolism Hepatology Immunohistochemistry Kinases Liver cancer Medicine Medicine & Public Health Metabolism Oncology Original Article Phenols Prostate cancer Protein binding Protein kinases Proteins Transcription factors Transplant Surgery |
| title | Androgen Receptor Stimulates Hexokinase 2 and Induces Glycolysis by PKA/CREB Signaling in Hepatocellular Carcinoma |
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