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Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis

In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR(®) assay) is an effective marker for highly enriching CCSCs...

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Autores principales: Chen, Sugong, Fisher, Robert C., Signs, Steven, Molina, L. Alex, Shenoy, Anitha K., Lopez, Maria-Cecilia, Baker, Henry V., Koomen, John M., Chen, Yi, Gittleman, Haley, Barnholtz-Sloan, Jill, Berg, Annamarie, Appelman, Henry D., Huang, Emina H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584153/
https://www.ncbi.nlm.nih.gov/pubmed/28881576
http://dx.doi.org/10.18632/oncotarget.9919
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author Chen, Sugong
Fisher, Robert C.
Signs, Steven
Molina, L. Alex
Shenoy, Anitha K.
Lopez, Maria-Cecilia
Baker, Henry V.
Koomen, John M.
Chen, Yi
Gittleman, Haley
Barnholtz-Sloan, Jill
Berg, Annamarie
Appelman, Henry D.
Huang, Emina H.
author_facet Chen, Sugong
Fisher, Robert C.
Signs, Steven
Molina, L. Alex
Shenoy, Anitha K.
Lopez, Maria-Cecilia
Baker, Henry V.
Koomen, John M.
Chen, Yi
Gittleman, Haley
Barnholtz-Sloan, Jill
Berg, Annamarie
Appelman, Henry D.
Huang, Emina H.
author_sort Chen, Sugong
collection PubMed
description In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR(®) assay) is an effective marker for highly enriching CCSCs for further evaluation. Here, we used comparative transcriptome and proteome approaches to identify signaling pathways overrepresented in the CCSC population. We found overexpression of several components of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway, including PI3KR2, a regulatory subunit of PI3K. LY294002, a PI3K inhibitor, defined the contribution of the PI3K/Akt/mTOR signaling pathway in CCSCs. LY294002-treated CCSCs showed decreases in proliferation, sphere formation and self-renewal, in phosphorylation-dependent activation of Akt, and in expression of cyclin D1. Inhibition of PI3K in vivo reduced tumorigenicity, increased detection of cleaved caspase 3, an indicator of apoptosis, and elevated expression of the inflammatory chemokine, CXCL8. Collectively, these results indicate that PI3K/Akt/mTOR signaling controls CCSC proliferation and CCSC survival, and suggests that it would be useful to develop therapeutic agents that target this signaling pathway.
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spelling pubmed-55841532017-09-06 Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis Chen, Sugong Fisher, Robert C. Signs, Steven Molina, L. Alex Shenoy, Anitha K. Lopez, Maria-Cecilia Baker, Henry V. Koomen, John M. Chen, Yi Gittleman, Haley Barnholtz-Sloan, Jill Berg, Annamarie Appelman, Henry D. Huang, Emina H. Oncotarget Research Paper In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR(®) assay) is an effective marker for highly enriching CCSCs for further evaluation. Here, we used comparative transcriptome and proteome approaches to identify signaling pathways overrepresented in the CCSC population. We found overexpression of several components of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway, including PI3KR2, a regulatory subunit of PI3K. LY294002, a PI3K inhibitor, defined the contribution of the PI3K/Akt/mTOR signaling pathway in CCSCs. LY294002-treated CCSCs showed decreases in proliferation, sphere formation and self-renewal, in phosphorylation-dependent activation of Akt, and in expression of cyclin D1. Inhibition of PI3K in vivo reduced tumorigenicity, increased detection of cleaved caspase 3, an indicator of apoptosis, and elevated expression of the inflammatory chemokine, CXCL8. Collectively, these results indicate that PI3K/Akt/mTOR signaling controls CCSC proliferation and CCSC survival, and suggests that it would be useful to develop therapeutic agents that target this signaling pathway. Impact Journals LLC 2016-06-08 /pmc/articles/PMC5584153/ /pubmed/28881576 http://dx.doi.org/10.18632/oncotarget.9919 Text en Copyright: © 2017 Chen et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Chen, Sugong
Fisher, Robert C.
Signs, Steven
Molina, L. Alex
Shenoy, Anitha K.
Lopez, Maria-Cecilia
Baker, Henry V.
Koomen, John M.
Chen, Yi
Gittleman, Haley
Barnholtz-Sloan, Jill
Berg, Annamarie
Appelman, Henry D.
Huang, Emina H.
Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis
title Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis
title_full Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis
title_fullStr Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis
title_full_unstemmed Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis
title_short Inhibition of PI3K/Akt/mTOR signaling in PI3KR2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis
title_sort inhibition of pi3k/akt/mtor signaling in pi3kr2-overexpressing colon cancer stem cells reduces tumor growth due to apoptosis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584153/
https://www.ncbi.nlm.nih.gov/pubmed/28881576
http://dx.doi.org/10.18632/oncotarget.9919
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