Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity
Klotho is a transmembrane protein, which can be shed and act as a circulating hormone and is involved in regulating cellular calcium levels and inhibition of the PI3K/AKT pathway. As a longevity hormone, it protects normal cells from oxidative stress, and as a tumor suppressor it inhibits growth of...
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| Veröffentlicht in: | Oncogene 2020-06, Vol.39 (24), p.4636-4649 |
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| creator | Shmulevich, Riva Nissim, Tsipi Ben-Kasus Wolf, Ido Merenbakh-Lamin, Keren Fishman, Daniel Sekler, Israel Rubinek, Tami |
| description | Klotho is a transmembrane protein, which can be shed and act as a circulating hormone and is involved in regulating cellular calcium levels and inhibition of the PI3K/AKT pathway. As a longevity hormone, it protects normal cells from oxidative stress, and as a tumor suppressor it inhibits growth of cancer cells. Mechanisms governing these differential activities have not been addressed. Altered cellular metabolism is a hallmark of cancer and dysregulation of mitochondrial activity is a hallmark of aging. We hypothesized that klotho exerts its differential effects through regulation of these two hallmarks. Treatment with klotho inhibited glycolysis, reduced mitochondrial activity and membrane potential only in cancer cells. Accordingly, global metabolic screen revealed that klotho altered pivotal metabolic pathways, amongst them glycolysis and tricarboxylic acid cycle in breast cancer cells. Alteration of metabolic activity and increased AMP/ATP ratio lead to LKB1-dependent AMPK activation. Indeed, klotho induced AMPK phosphorylation; furthermore, inhibition of LKB1 partially abolished klotho’s tumor suppressor activity. By diminishing deltapsi (Δψ) klotho also inhibited mitochondria Ca
2+
shuttling thereby impairing mitochondria communication with SOCE leading to reduced Ca
2+
influx by SOCE channels. The reduced SOCE was followed by ER Ca
2+
depletion and stress. These data delineate mechanisms mediating the differential effects of klotho toward cancer versus normal cells, and indicate klotho as a potent regulator of metabolic activity. |
| doi_str_mv | 10.1038/s41388-020-1313-5 |
| format | Article |
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2+
shuttling thereby impairing mitochondria communication with SOCE leading to reduced Ca
2+
influx by SOCE channels. The reduced SOCE was followed by ER Ca
2+
depletion and stress. These data delineate mechanisms mediating the differential effects of klotho toward cancer versus normal cells, and indicate klotho as a potent regulator of metabolic activity.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-020-1313-5</identifier><identifier>PMID: 32398866</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>1-Phosphatidylinositol 3-kinase ; 13/95 ; 14/34 ; 631/443/319/333/1465 ; 631/67/2327 ; 631/80/84 ; 9/10 ; 96/106 ; Aging ; AKT protein ; AMP ; Animals ; Apoptosis ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Calcium (mitochondrial) ; Calcium - metabolism ; Calcium channels ; Calcium influx ; Calcium Signaling ; Cancer ; Cancer cells ; Care and treatment ; Cell Biology ; Glucose metabolism ; Glucuronidase - genetics ; Glucuronidase - metabolism ; Glycolysis ; Human Genetics ; Humans ; Internal Medicine ; Klotho protein ; LKB1 protein ; MCF-7 Cells ; Medicine ; Medicine & Public Health ; Membrane potential ; Metabolic pathways ; Metabolism ; Mice ; Mitochondria ; Mitochondria - genetics ; Mitochondria - metabolism ; Mitochondria - pathology ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Oncology ; Oxidative stress ; Phosphorylation ; Physiological aspects ; Tricarboxylic acid cycle ; Tumor suppressor genes</subject><ispartof>Oncogene, 2020-06, Vol.39 (24), p.4636-4649</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c434t-92af971c94afae240f7c2668b1fb9f54d0e360638babb65ca49150e4f2c44b073</citedby><cites>FETCH-LOGICAL-c434t-92af971c94afae240f7c2668b1fb9f54d0e360638babb65ca49150e4f2c44b073</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/s41388-020-1313-5$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-020-1313-5$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32398866$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shmulevich, Riva</creatorcontrib><creatorcontrib>Nissim, Tsipi Ben-Kasus</creatorcontrib><creatorcontrib>Wolf, Ido</creatorcontrib><creatorcontrib>Merenbakh-Lamin, Keren</creatorcontrib><creatorcontrib>Fishman, Daniel</creatorcontrib><creatorcontrib>Sekler, Israel</creatorcontrib><creatorcontrib>Rubinek, Tami</creatorcontrib><title>Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Klotho is a transmembrane protein, which can be shed and act as a circulating hormone and is involved in regulating cellular calcium levels and inhibition of the PI3K/AKT pathway. As a longevity hormone, it protects normal cells from oxidative stress, and as a tumor suppressor it inhibits growth of cancer cells. Mechanisms governing these differential activities have not been addressed. Altered cellular metabolism is a hallmark of cancer and dysregulation of mitochondrial activity is a hallmark of aging. We hypothesized that klotho exerts its differential effects through regulation of these two hallmarks. Treatment with klotho inhibited glycolysis, reduced mitochondrial activity and membrane potential only in cancer cells. Accordingly, global metabolic screen revealed that klotho altered pivotal metabolic pathways, amongst them glycolysis and tricarboxylic acid cycle in breast cancer cells. Alteration of metabolic activity and increased AMP/ATP ratio lead to LKB1-dependent AMPK activation. Indeed, klotho induced AMPK phosphorylation; furthermore, inhibition of LKB1 partially abolished klotho’s tumor suppressor activity. By diminishing deltapsi (Δψ) klotho also inhibited mitochondria Ca
2+
shuttling thereby impairing mitochondria communication with SOCE leading to reduced Ca
2+
influx by SOCE channels. The reduced SOCE was followed by ER Ca
2+
depletion and stress. These data delineate mechanisms mediating the differential effects of klotho toward cancer versus normal cells, and indicate klotho as a potent regulator of metabolic activity.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>13/95</subject><subject>14/34</subject><subject>631/443/319/333/1465</subject><subject>631/67/2327</subject><subject>631/80/84</subject><subject>9/10</subject><subject>96/106</subject><subject>Aging</subject><subject>AKT protein</subject><subject>AMP</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Calcium (mitochondrial)</subject><subject>Calcium - metabolism</subject><subject>Calcium channels</subject><subject>Calcium influx</subject><subject>Calcium Signaling</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Glucose metabolism</subject><subject>Glucuronidase - genetics</subject><subject>Glucuronidase - metabolism</subject><subject>Glycolysis</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Klotho protein</subject><subject>LKB1 protein</subject><subject>MCF-7 Cells</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane potential</subject><subject>Metabolic pathways</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mitochondria</subject><subject>Mitochondria - genetics</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - pathology</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Oncology</subject><subject>Oxidative stress</subject><subject>Phosphorylation</subject><subject>Physiological aspects</subject><subject>Tricarboxylic acid cycle</subject><subject>Tumor suppressor genes</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kU1rFTEUhoMo9lr9AW4k4HpqvmeyLMUvLLjRdTiTSe6kZCY1ySiF_nhze6tFUMkikDzvOTl5EHpJyRklfHhTBOXD0BFGOsop7-QjtKOiV52UWjxGO6Il6TTj7AQ9K-WKENJrwp6iE864Hgalduj2U0x1Tji7HyG7gq2LcYuQ8eIqjCmGsuDk8ZgdlIotrNblO6jgOue07WcMsboMNaT1QFqINmwLLvNWawzrHsM64SXUZOe0TjlAxGBr-B7qzXP0xEMs7sX9foq-vnv75eJDd_n5_ceL88vOCi5qmwC87qnVAjw4JojvLVNqGKkftZdiIo4rovgwwjgqaUFoKokTnlkhRtLzU_T6WPc6p2-bK9VcpS2vraVh7bt6PshB_5-ijArNJXmg9hCdCatPNYNdQrHmXDHFuVZ3Hc_-QrU1uSXYtDof2vkfAXoM2JxKyc6b6xwWyDeGEnOQbY6yTZNtDrKNbJlX9w_exsVNvxO_7DaAHYHSrta9yw8T_bvqT6b7tMI</recordid><startdate>20200611</startdate><enddate>20200611</enddate><creator>Shmulevich, Riva</creator><creator>Nissim, Tsipi Ben-Kasus</creator><creator>Wolf, Ido</creator><creator>Merenbakh-Lamin, Keren</creator><creator>Fishman, Daniel</creator><creator>Sekler, Israel</creator><creator>Rubinek, Tami</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></search><sort><creationdate>20200611</creationdate><title>Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity</title><author>Shmulevich, Riva ; Nissim, Tsipi Ben-Kasus ; Wolf, Ido ; Merenbakh-Lamin, Keren ; Fishman, Daniel ; Sekler, Israel ; Rubinek, Tami</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c434t-92af971c94afae240f7c2668b1fb9f54d0e360638babb65ca49150e4f2c44b073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>13/95</topic><topic>14/34</topic><topic>631/443/319/333/1465</topic><topic>631/67/2327</topic><topic>631/80/84</topic><topic>9/10</topic><topic>96/106</topic><topic>Aging</topic><topic>AKT protein</topic><topic>AMP</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Calcium (mitochondrial)</topic><topic>Calcium - metabolism</topic><topic>Calcium channels</topic><topic>Calcium influx</topic><topic>Calcium Signaling</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Glucose metabolism</topic><topic>Glucuronidase - genetics</topic><topic>Glucuronidase - metabolism</topic><topic>Glycolysis</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Klotho protein</topic><topic>LKB1 protein</topic><topic>MCF-7 Cells</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Membrane potential</topic><topic>Metabolic pathways</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mitochondria</topic><topic>Mitochondria - genetics</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria - pathology</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Oncology</topic><topic>Oxidative stress</topic><topic>Phosphorylation</topic><topic>Physiological aspects</topic><topic>Tricarboxylic acid cycle</topic><topic>Tumor suppressor genes</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shmulevich, Riva</creatorcontrib><creatorcontrib>Nissim, Tsipi Ben-Kasus</creatorcontrib><creatorcontrib>Wolf, Ido</creatorcontrib><creatorcontrib>Merenbakh-Lamin, Keren</creatorcontrib><creatorcontrib>Fishman, Daniel</creatorcontrib><creatorcontrib>Sekler, Israel</creatorcontrib><creatorcontrib>Rubinek, Tami</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shmulevich, Riva</au><au>Nissim, Tsipi Ben-Kasus</au><au>Wolf, Ido</au><au>Merenbakh-Lamin, Keren</au><au>Fishman, Daniel</au><au>Sekler, Israel</au><au>Rubinek, Tami</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2020-06-11</date><risdate>2020</risdate><volume>39</volume><issue>24</issue><spage>4636</spage><epage>4649</epage><pages>4636-4649</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Klotho is a transmembrane protein, which can be shed and act as a circulating hormone and is involved in regulating cellular calcium levels and inhibition of the PI3K/AKT pathway. As a longevity hormone, it protects normal cells from oxidative stress, and as a tumor suppressor it inhibits growth of cancer cells. Mechanisms governing these differential activities have not been addressed. Altered cellular metabolism is a hallmark of cancer and dysregulation of mitochondrial activity is a hallmark of aging. We hypothesized that klotho exerts its differential effects through regulation of these two hallmarks. Treatment with klotho inhibited glycolysis, reduced mitochondrial activity and membrane potential only in cancer cells. Accordingly, global metabolic screen revealed that klotho altered pivotal metabolic pathways, amongst them glycolysis and tricarboxylic acid cycle in breast cancer cells. Alteration of metabolic activity and increased AMP/ATP ratio lead to LKB1-dependent AMPK activation. Indeed, klotho induced AMPK phosphorylation; furthermore, inhibition of LKB1 partially abolished klotho’s tumor suppressor activity. By diminishing deltapsi (Δψ) klotho also inhibited mitochondria Ca
2+
shuttling thereby impairing mitochondria communication with SOCE leading to reduced Ca
2+
influx by SOCE channels. The reduced SOCE was followed by ER Ca
2+
depletion and stress. These data delineate mechanisms mediating the differential effects of klotho toward cancer versus normal cells, and indicate klotho as a potent regulator of metabolic activity.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32398866</pmid><doi>10.1038/s41388-020-1313-5</doi><tpages>14</tpages></addata></record> |
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| ispartof | Oncogene, 2020-06, Vol.39 (24), p.4636-4649 |
| issn | 0950-9232 1476-5594 |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | 1-Phosphatidylinositol 3-kinase 13/95 14/34 631/443/319/333/1465 631/67/2327 631/80/84 9/10 96/106 Aging AKT protein AMP Animals Apoptosis Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Calcium (mitochondrial) Calcium - metabolism Calcium channels Calcium influx Calcium Signaling Cancer Cancer cells Care and treatment Cell Biology Glucose metabolism Glucuronidase - genetics Glucuronidase - metabolism Glycolysis Human Genetics Humans Internal Medicine Klotho protein LKB1 protein MCF-7 Cells Medicine Medicine & Public Health Membrane potential Metabolic pathways Metabolism Mice Mitochondria Mitochondria - genetics Mitochondria - metabolism Mitochondria - pathology Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Oncology Oxidative stress Phosphorylation Physiological aspects Tricarboxylic acid cycle Tumor suppressor genes |
| title | Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity |
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