Cargando…
Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo
We observed a co-upregulation of the insulin-like growth factor receptor (IGF-1R)/AKT/mammalian target of rapamycin (mTOR) [InAT] axis and the mevalonate-isoprenoid biosynthesis (MIB) pathways in colorectal cancer stem cells (CSCs) in an unbiased approach. Hence, we hypothesized that the InAT axis m...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558155/ https://www.ncbi.nlm.nih.gov/pubmed/25895029 |
_version_ | 1782388588604817408 |
---|---|
author | Sharon, Chetna Baranwal, Somesh Patel, Nirmita J. Rodriguez-Agudo, Daniel Pandak, William M. Majumdar, Adhip PN Krystal, Geoffrey Patel, Bhaumik B. |
author_facet | Sharon, Chetna Baranwal, Somesh Patel, Nirmita J. Rodriguez-Agudo, Daniel Pandak, William M. Majumdar, Adhip PN Krystal, Geoffrey Patel, Bhaumik B. |
author_sort | Sharon, Chetna |
collection | PubMed |
description | We observed a co-upregulation of the insulin-like growth factor receptor (IGF-1R)/AKT/mammalian target of rapamycin (mTOR) [InAT] axis and the mevalonate-isoprenoid biosynthesis (MIB) pathways in colorectal cancer stem cells (CSCs) in an unbiased approach. Hence, we hypothesized that the InAT axis might regulate the MIB pathway to govern colorectal CSCs growth. Stimulation (IGF-1) or inhibition (IGF-1R depletion and pharmacological inhibition of IGF-1R/mTOR) of the InAT axis produced induction or attenuation of CSC growth as well as expression of CSC markers and self-renewal factors respectively. Intriguingly, activation of the InAT axis (IGF-1) caused significant upregulation of the MIB pathway genes (both mRNA and protein); while its inhibition produced the opposite effects in colonospheres. More importantly, supplementation with dimethylallyl- and farnesyl-PP, MIB metabolites downstream of isopentenyl-diphosphate delta isomerase (IDI), but not mevalonate and isopentenyl-pp that are upstream of IDI, resulted in a near-complete reversal of the suppressive effect of the InAT axis inhibitors on CSCs growth. The latter findings suggest a specific regulation of the MIB pathway by the InAT axis distal to the target of statins that inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Effects of IGF-1R inhibition on colonic CSCs proliferation and the MIB pathway were confirmed in an ‘in vivo’ HCT-116 xenograft model. These observations establish a novel mechanistic link between the InAT axis that is commonly deregulated in colorectal cancer and the MIB pathway in regulation of colonic CSCs growth. Hence, the InAT-MIB corridor is a novel target for developing paradigm shifting optimum anti-CSCs therapies for colorectal cancer. |
format | Online Article Text |
id | pubmed-4558155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-45581552015-09-09 Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo Sharon, Chetna Baranwal, Somesh Patel, Nirmita J. Rodriguez-Agudo, Daniel Pandak, William M. Majumdar, Adhip PN Krystal, Geoffrey Patel, Bhaumik B. Oncotarget Research Paper We observed a co-upregulation of the insulin-like growth factor receptor (IGF-1R)/AKT/mammalian target of rapamycin (mTOR) [InAT] axis and the mevalonate-isoprenoid biosynthesis (MIB) pathways in colorectal cancer stem cells (CSCs) in an unbiased approach. Hence, we hypothesized that the InAT axis might regulate the MIB pathway to govern colorectal CSCs growth. Stimulation (IGF-1) or inhibition (IGF-1R depletion and pharmacological inhibition of IGF-1R/mTOR) of the InAT axis produced induction or attenuation of CSC growth as well as expression of CSC markers and self-renewal factors respectively. Intriguingly, activation of the InAT axis (IGF-1) caused significant upregulation of the MIB pathway genes (both mRNA and protein); while its inhibition produced the opposite effects in colonospheres. More importantly, supplementation with dimethylallyl- and farnesyl-PP, MIB metabolites downstream of isopentenyl-diphosphate delta isomerase (IDI), but not mevalonate and isopentenyl-pp that are upstream of IDI, resulted in a near-complete reversal of the suppressive effect of the InAT axis inhibitors on CSCs growth. The latter findings suggest a specific regulation of the MIB pathway by the InAT axis distal to the target of statins that inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). Effects of IGF-1R inhibition on colonic CSCs proliferation and the MIB pathway were confirmed in an ‘in vivo’ HCT-116 xenograft model. These observations establish a novel mechanistic link between the InAT axis that is commonly deregulated in colorectal cancer and the MIB pathway in regulation of colonic CSCs growth. Hence, the InAT-MIB corridor is a novel target for developing paradigm shifting optimum anti-CSCs therapies for colorectal cancer. Impact Journals LLC 2015-03-29 /pmc/articles/PMC4558155/ /pubmed/25895029 Text en Copyright: © 2015 Sharon et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Sharon, Chetna Baranwal, Somesh Patel, Nirmita J. Rodriguez-Agudo, Daniel Pandak, William M. Majumdar, Adhip PN Krystal, Geoffrey Patel, Bhaumik B. Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo |
title | Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo |
title_full | Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo |
title_fullStr | Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo |
title_full_unstemmed | Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo |
title_short | Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo |
title_sort | inhibition of insulin-like growth factor receptor/akt/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558155/ https://www.ncbi.nlm.nih.gov/pubmed/25895029 |
work_keys_str_mv | AT sharonchetna inhibitionofinsulinlikegrowthfactorreceptoraktmammaliantargetofrapamycinaxistargetscolorectalcancerstemcellsbyattenuatingmevalonateisoprenoidpathwayinvitroandinvivo AT baranwalsomesh inhibitionofinsulinlikegrowthfactorreceptoraktmammaliantargetofrapamycinaxistargetscolorectalcancerstemcellsbyattenuatingmevalonateisoprenoidpathwayinvitroandinvivo AT patelnirmitaj inhibitionofinsulinlikegrowthfactorreceptoraktmammaliantargetofrapamycinaxistargetscolorectalcancerstemcellsbyattenuatingmevalonateisoprenoidpathwayinvitroandinvivo AT rodriguezagudodaniel inhibitionofinsulinlikegrowthfactorreceptoraktmammaliantargetofrapamycinaxistargetscolorectalcancerstemcellsbyattenuatingmevalonateisoprenoidpathwayinvitroandinvivo AT pandakwilliamm inhibitionofinsulinlikegrowthfactorreceptoraktmammaliantargetofrapamycinaxistargetscolorectalcancerstemcellsbyattenuatingmevalonateisoprenoidpathwayinvitroandinvivo AT majumdaradhippn inhibitionofinsulinlikegrowthfactorreceptoraktmammaliantargetofrapamycinaxistargetscolorectalcancerstemcellsbyattenuatingmevalonateisoprenoidpathwayinvitroandinvivo AT krystalgeoffrey inhibitionofinsulinlikegrowthfactorreceptoraktmammaliantargetofrapamycinaxistargetscolorectalcancerstemcellsbyattenuatingmevalonateisoprenoidpathwayinvitroandinvivo AT patelbhaumikb inhibitionofinsulinlikegrowthfactorreceptoraktmammaliantargetofrapamycinaxistargetscolorectalcancerstemcellsbyattenuatingmevalonateisoprenoidpathwayinvitroandinvivo |