Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis
Extracellular ATP has been shown to either inhibit or promote cancer growth and migration; however, the mechanism underlying this discrepancy remained elusive. Here we demonstrate the divergent roles of ATP and adenosine released by bone osteocytes on breast cancers. We showed that conditioned media...
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| description | Extracellular ATP has been shown to either inhibit or promote cancer growth and migration; however, the mechanism underlying this discrepancy remained elusive. Here we demonstrate the divergent roles of ATP and adenosine released by bone osteocytes on breast cancers. We showed that conditioned media (CM) collected from osteocytes treated with alendronate (AD), a bisphosphonate drug, inhibited the migration of human breast cancer MDA-MB-231 cells. Removal of the extracellular ATP by apyrase in CM abolished this effect, suggesting the involvement of ATP. ATP exerted its inhibitory effect through the activation of purinergic P2X receptor signaling in breast cancer cells evidenced by the attenuation of the inhibition by an antagonist, oxidized ATP, as well as knocking down P2X7 with small interfering RNA (siRNA), and the inhibition of migration by an agonist, BzATP. Intriguingly, ATP had a biphasic effect on breast cancer cells—lower dosage inhibited but higher dosage promoted its migration. The stimulatory effect on migration was blocked by an adenosine receptor antagonist, MRS1754, ARL67156, an ecto-ATPase inhibitor, and A
2A
receptor siRNA, suggesting that in contrast to ATP, adenosine, a metabolic product of ATP, promoted migration of breast cancer cells. Consistently, non-hydrolyzable ATP, ATPγS, only inhibited but did not promote cancer cell migration. ATP also had a similar inhibitory effect on the Py8119 mouse mammary carcinoma cells; however, adenosine had no effect owing to the absence of the A
2A
receptor. Consistently, ATPγS inhibited, whereas adenosine promoted anchorage-independent growth of MDA-MB-231 cells. Our
in vivo
xenograft study showed a significant delay of tumor growth with the treatment of ATPγS. Moreover, the extent of bone metastasis in a mouse intratibial model was significantly reduced with the treatment of ATPγS. Together, our results suggest the distinct roles of ATP and adenosine released by osteocytes and the activation of corresponding receptors P2X7 and A
2A
signaling on breast cancer cell growth, migration and bone metastasis. |
| doi_str_mv | 10.1038/onc.2014.113 |
| format | Article |
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2A
receptor siRNA, suggesting that in contrast to ATP, adenosine, a metabolic product of ATP, promoted migration of breast cancer cells. Consistently, non-hydrolyzable ATP, ATPγS, only inhibited but did not promote cancer cell migration. ATP also had a similar inhibitory effect on the Py8119 mouse mammary carcinoma cells; however, adenosine had no effect owing to the absence of the A
2A
receptor. Consistently, ATPγS inhibited, whereas adenosine promoted anchorage-independent growth of MDA-MB-231 cells. Our
in vivo
xenograft study showed a significant delay of tumor growth with the treatment of ATPγS. Moreover, the extent of bone metastasis in a mouse intratibial model was significantly reduced with the treatment of ATPγS. Together, our results suggest the distinct roles of ATP and adenosine released by osteocytes and the activation of corresponding receptors P2X7 and A
2A
signaling on breast cancer cell growth, migration and bone metastasis.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2014.113</identifier><identifier>PMID: 24837364</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 14/34 ; 14/63 ; 59 ; 59/5 ; 631/67/322 ; Adenosine ; Adenosine - metabolism ; Adenosine triphosphatase ; Adenosine triphosphate ; Adenosine Triphosphate - analogs & derivatives ; Adenosine Triphosphate - metabolism ; Adenosine Triphosphate - pharmacology ; Alendronate - pharmacology ; Alendronic acid ; Animals ; Apoptosis ; Apyrase ; Apyrase - pharmacology ; Bisphosphonates ; Bone cancer ; Bone Density Conservation Agents - pharmacology ; Bone growth ; Bone Neoplasms - secondary ; Bones ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Carcinoma ; Cell adhesion & migration ; Cell Biology ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell Proliferation ; Complications and side effects ; Development and progression ; Female ; Genetic aspects ; Health aspects ; Human Genetics ; Humans ; Internal Medicine ; Mammary gland ; Medicine ; Medicine & Public Health ; Metastases ; Metastasis ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Transplantation ; Nucleotides ; Oncology ; original-article ; Osteocytes ; Osteocytes - metabolism ; Purine P2X receptors ; Receptor, Adenosine A2A - genetics ; Receptor, Adenosine A2A - metabolism ; Receptors, Purinergic P2X - genetics ; Receptors, Purinergic P2X - metabolism ; RNA Interference ; RNA, Small Interfering ; Signal Transduction ; siRNA ; Transplantation, Heterologous ; Xenografts</subject><ispartof>Oncogene, 2015-04, Vol.34 (14), p.1831-1842</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Apr 2, 2015</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c609t-bed84cb9222b183098612cf1bf960eac7deb079a9c05476b36aec5da3d45c5d23</citedby><cites>FETCH-LOGICAL-c609t-bed84cb9222b183098612cf1bf960eac7deb079a9c05476b36aec5da3d45c5d23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2014.113$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2014.113$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24837364$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhou, J Z</creatorcontrib><creatorcontrib>Riquelme, M A</creatorcontrib><creatorcontrib>Gao, X</creatorcontrib><creatorcontrib>Ellies, L G</creatorcontrib><creatorcontrib>Sun, L Z</creatorcontrib><creatorcontrib>Jiang, J X</creatorcontrib><title>Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Extracellular ATP has been shown to either inhibit or promote cancer growth and migration; however, the mechanism underlying this discrepancy remained elusive. Here we demonstrate the divergent roles of ATP and adenosine released by bone osteocytes on breast cancers. We showed that conditioned media (CM) collected from osteocytes treated with alendronate (AD), a bisphosphonate drug, inhibited the migration of human breast cancer MDA-MB-231 cells. Removal of the extracellular ATP by apyrase in CM abolished this effect, suggesting the involvement of ATP. ATP exerted its inhibitory effect through the activation of purinergic P2X receptor signaling in breast cancer cells evidenced by the attenuation of the inhibition by an antagonist, oxidized ATP, as well as knocking down P2X7 with small interfering RNA (siRNA), and the inhibition of migration by an agonist, BzATP. Intriguingly, ATP had a biphasic effect on breast cancer cells—lower dosage inhibited but higher dosage promoted its migration. The stimulatory effect on migration was blocked by an adenosine receptor antagonist, MRS1754, ARL67156, an ecto-ATPase inhibitor, and A
2A
receptor siRNA, suggesting that in contrast to ATP, adenosine, a metabolic product of ATP, promoted migration of breast cancer cells. Consistently, non-hydrolyzable ATP, ATPγS, only inhibited but did not promote cancer cell migration. ATP also had a similar inhibitory effect on the Py8119 mouse mammary carcinoma cells; however, adenosine had no effect owing to the absence of the A
2A
receptor. Consistently, ATPγS inhibited, whereas adenosine promoted anchorage-independent growth of MDA-MB-231 cells. Our
in vivo
xenograft study showed a significant delay of tumor growth with the treatment of ATPγS. Moreover, the extent of bone metastasis in a mouse intratibial model was significantly reduced with the treatment of ATPγS. Together, our results suggest the distinct roles of ATP and adenosine released by osteocytes and the activation of corresponding receptors P2X7 and A
2A
signaling on breast cancer cell growth, migration and bone metastasis.</description><subject>13</subject><subject>13/1</subject><subject>14/34</subject><subject>14/63</subject><subject>59</subject><subject>59/5</subject><subject>631/67/322</subject><subject>Adenosine</subject><subject>Adenosine - metabolism</subject><subject>Adenosine triphosphatase</subject><subject>Adenosine triphosphate</subject><subject>Adenosine Triphosphate - analogs & derivatives</subject><subject>Adenosine Triphosphate - metabolism</subject><subject>Adenosine Triphosphate - pharmacology</subject><subject>Alendronate - pharmacology</subject><subject>Alendronic acid</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apyrase</subject><subject>Apyrase - pharmacology</subject><subject>Bisphosphonates</subject><subject>Bone cancer</subject><subject>Bone Density Conservation Agents - pharmacology</subject><subject>Bone growth</subject><subject>Bone Neoplasms - secondary</subject><subject>Bones</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Carcinoma</subject><subject>Cell adhesion & migration</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell Proliferation</subject><subject>Complications and side effects</subject><subject>Development and progression</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Mammary gland</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Nude</subject><subject>Neoplasm Transplantation</subject><subject>Nucleotides</subject><subject>Oncology</subject><subject>original-article</subject><subject>Osteocytes</subject><subject>Osteocytes - metabolism</subject><subject>Purine P2X receptors</subject><subject>Receptor, Adenosine A2A - genetics</subject><subject>Receptor, Adenosine A2A - metabolism</subject><subject>Receptors, Purinergic P2X - genetics</subject><subject>Receptors, Purinergic P2X - metabolism</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering</subject><subject>Signal Transduction</subject><subject>siRNA</subject><subject>Transplantation, Heterologous</subject><subject>Xenografts</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNks1rFTEUxYMo9rW6cy0BNy46z3xNJtkIpX5CwY2uQyZz5zVlJnkmGeX99-bx2lpLka4u3PPjJOdyEHpFyZoSrt7F4NaMULGmlD9BKyo62bStFk_RiuiWNJpxdoSOc74ihHSasOfoiAnFOy7FCsUPfhwhQSjeTtjPW-sKjiO2A4SYfQAcFjdBLH6AjBNMYDMMuN_hmAtEtyt1HQPuUxUKdjY4SHiT4u9yiW2oZKweM5Sq2uzzC_RstFOGl9fzBP349PH7-Zfm4tvnr-dnF42TRJemh0EJ12vGWE8VJ1pJytxI-1FLAtZ1A_Q1jNWOtDVwz6UF1w6WD6Ktk_ET9P7gu136GQZXAyY7mW3ys007E603_yrBX5pN_GUEp20nZTV4e22Q4s8FcjGzzw6myQaISzZUdpK3VCvxCFRqxXkn9q5v7qFXcUmhXsIwzqnktCPqf1T1UpwKIvlfamMnMD6MsQZx-6fNmaCEcqU1rdTpgXIp5pxgvL0BJWZfIFMLZPYFMrVAFX9992638E1jKtAcgFylsIF0528PGf4BKajQWA</recordid><startdate>20150402</startdate><enddate>20150402</enddate><creator>Zhou, J Z</creator><creator>Riquelme, M A</creator><creator>Gao, X</creator><creator>Ellies, L G</creator><creator>Sun, L Z</creator><creator>Jiang, J X</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>7QP</scope><scope>5PM</scope></search><sort><creationdate>20150402</creationdate><title>Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis</title><author>Zhou, J Z ; Riquelme, M A ; Gao, X ; Ellies, L G ; Sun, L Z ; Jiang, J X</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c609t-bed84cb9222b183098612cf1bf960eac7deb079a9c05476b36aec5da3d45c5d23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>13</topic><topic>13/1</topic><topic>14/34</topic><topic>14/63</topic><topic>59</topic><topic>59/5</topic><topic>631/67/322</topic><topic>Adenosine</topic><topic>Adenosine - metabolism</topic><topic>Adenosine triphosphatase</topic><topic>Adenosine triphosphate</topic><topic>Adenosine Triphosphate - analogs & derivatives</topic><topic>Adenosine Triphosphate - metabolism</topic><topic>Adenosine Triphosphate - pharmacology</topic><topic>Alendronate - pharmacology</topic><topic>Alendronic acid</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apyrase</topic><topic>Apyrase - pharmacology</topic><topic>Bisphosphonates</topic><topic>Bone cancer</topic><topic>Bone Density Conservation Agents - pharmacology</topic><topic>Bone growth</topic><topic>Bone Neoplasms - secondary</topic><topic>Bones</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - pathology</topic><topic>Carcinoma</topic><topic>Cell adhesion & migration</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement - drug effects</topic><topic>Cell Proliferation</topic><topic>Complications and side effects</topic><topic>Development and progression</topic><topic>Female</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Mammary gland</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Nude</topic><topic>Neoplasm Transplantation</topic><topic>Nucleotides</topic><topic>Oncology</topic><topic>original-article</topic><topic>Osteocytes</topic><topic>Osteocytes - 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Academic</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhou, J Z</au><au>Riquelme, M A</au><au>Gao, X</au><au>Ellies, L G</au><au>Sun, L Z</au><au>Jiang, J X</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2015-04-02</date><risdate>2015</risdate><volume>34</volume><issue>14</issue><spage>1831</spage><epage>1842</epage><pages>1831-1842</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Extracellular ATP has been shown to either inhibit or promote cancer growth and migration; however, the mechanism underlying this discrepancy remained elusive. Here we demonstrate the divergent roles of ATP and adenosine released by bone osteocytes on breast cancers. We showed that conditioned media (CM) collected from osteocytes treated with alendronate (AD), a bisphosphonate drug, inhibited the migration of human breast cancer MDA-MB-231 cells. Removal of the extracellular ATP by apyrase in CM abolished this effect, suggesting the involvement of ATP. ATP exerted its inhibitory effect through the activation of purinergic P2X receptor signaling in breast cancer cells evidenced by the attenuation of the inhibition by an antagonist, oxidized ATP, as well as knocking down P2X7 with small interfering RNA (siRNA), and the inhibition of migration by an agonist, BzATP. Intriguingly, ATP had a biphasic effect on breast cancer cells—lower dosage inhibited but higher dosage promoted its migration. The stimulatory effect on migration was blocked by an adenosine receptor antagonist, MRS1754, ARL67156, an ecto-ATPase inhibitor, and A
2A
receptor siRNA, suggesting that in contrast to ATP, adenosine, a metabolic product of ATP, promoted migration of breast cancer cells. Consistently, non-hydrolyzable ATP, ATPγS, only inhibited but did not promote cancer cell migration. ATP also had a similar inhibitory effect on the Py8119 mouse mammary carcinoma cells; however, adenosine had no effect owing to the absence of the A
2A
receptor. Consistently, ATPγS inhibited, whereas adenosine promoted anchorage-independent growth of MDA-MB-231 cells. Our
in vivo
xenograft study showed a significant delay of tumor growth with the treatment of ATPγS. Moreover, the extent of bone metastasis in a mouse intratibial model was significantly reduced with the treatment of ATPγS. Together, our results suggest the distinct roles of ATP and adenosine released by osteocytes and the activation of corresponding receptors P2X7 and A
2A
signaling on breast cancer cell growth, migration and bone metastasis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24837364</pmid><doi>10.1038/onc.2014.113</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | 13 13/1 14/34 14/63 59 59/5 631/67/322 Adenosine Adenosine - metabolism Adenosine triphosphatase Adenosine triphosphate Adenosine Triphosphate - analogs & derivatives Adenosine Triphosphate - metabolism Adenosine Triphosphate - pharmacology Alendronate - pharmacology Alendronic acid Animals Apoptosis Apyrase Apyrase - pharmacology Bisphosphonates Bone cancer Bone Density Conservation Agents - pharmacology Bone growth Bone Neoplasms - secondary Bones Breast cancer Breast Neoplasms - genetics Breast Neoplasms - pathology Carcinoma Cell adhesion & migration Cell Biology Cell Line, Tumor Cell migration Cell Movement - drug effects Cell Proliferation Complications and side effects Development and progression Female Genetic aspects Health aspects Human Genetics Humans Internal Medicine Mammary gland Medicine Medicine & Public Health Metastases Metastasis Mice Mice, Inbred C57BL Mice, Nude Neoplasm Transplantation Nucleotides Oncology original-article Osteocytes Osteocytes - metabolism Purine P2X receptors Receptor, Adenosine A2A - genetics Receptor, Adenosine A2A - metabolism Receptors, Purinergic P2X - genetics Receptors, Purinergic P2X - metabolism RNA Interference RNA, Small Interfering Signal Transduction siRNA Transplantation, Heterologous Xenografts |
| title | Differential impact of adenosine nucleotides released by osteocytes on breast cancer growth and bone metastasis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T20%3A58%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Differential%20impact%20of%20adenosine%20nucleotides%20released%20by%20osteocytes%20on%20breast%20cancer%20growth%20and%20bone%20metastasis&rft.jtitle=Oncogene&rft.au=Zhou,%20J%20Z&rft.date=2015-04-02&rft.volume=34&rft.issue=14&rft.spage=1831&rft.epage=1842&rft.pages=1831-1842&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/onc.2014.113&rft_dat=%3Cgale_pubme%3EA410138991%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1668314063&rft_id=info:pmid/24837364&rft_galeid=A410138991&rfr_iscdi=true |