Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells (CSCs) that self-renew and often escape ther...

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Autores: Bort Bueno, Alicia Carmen|||0000-0003-1490-5823, Sánchez Gómez, Belén|||0000-0003-0971-1522, Mateos Gómez, Pedro Antonio|||0000-0002-5539-2289, Vara Ciruelos, Diana|||0000-0002-9508-2648, Rodríguez Henche, María de las Nieves|||0000-0001-9798-359X, Díaz-Laviada Marturet, Inés Cecilia|||0000-0001-9704-4373
Formato: artículo
Fecha de publicación:2019
País:España
Recursos:Universidad de Alcalá (UAH)
Repositorio:e_Buah Biblioteca Digital Universidad de Alcalá
Idioma:inglés
OAI Identifier:oai:ebuah.uah.es:10017/60095
Acesso em linha:http://hdl.handle.net/10017/60095
https://dx.doi.org/10.1002/1878-0261.12488
Access Level:acceso abierto
Palavra-chave:AMP-activated kinase
cancer stem cells
drug resistance
hepatocellular carcinoma
sorafenib
Medicina
Medicine
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spelling Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenibBort Bueno, Alicia Carmen|||0000-0003-1490-5823Sánchez Gómez, Belén|||0000-0003-0971-1522Mateos Gómez, Pedro Antonio|||0000-0002-5539-2289Vara Ciruelos, Diana|||0000-0002-9508-2648Rodríguez Henche, María de las Nieves|||0000-0001-9798-359XDíaz-Laviada Marturet, Inés Cecilia|||0000-0001-9704-4373AMP-activated kinasecancer stem cellsdrug resistancehepatocellular carcinomasorafenibMedicinaMedicineHepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells (CSCs) that self-renew and often escape therapy. The key metabolic sensor AMP-activated kinase (AMPK) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance (ALDH1A1, ABCB1A) and stem cell (CD133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib-induced cell death. We report that sorafenib-resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC, compared with the parental cells. Interestingly, AMPK knockdown with siRNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib-induced cell death. Conversely, the upregulation of AMPK, either by transfection or by pharmacological activation with A-769662, decreased the expression of ALDH1A1, ABCB1A, CD133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia-inducible factor HIF-1? as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem-like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC.Fundación Tatiana Pérez de Guzmán el Bueno20192019-04-15journal articlehttp://purl.org/coar/resource_type/c_6501NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10017/60095https://dx.doi.org/10.1002/1878-0261.12488reponame:e_Buah Biblioteca Digital Universidad de Alcaláinstname:Universidad de Alcalá (UAH)InglésengFT Not available 2013-01open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ebuah.uah.es:10017/600952026-06-18T11:13:07Z
dc.title.none.fl_str_mv Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
title Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
spellingShingle Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
Bort Bueno, Alicia Carmen|||0000-0003-1490-5823
AMP-activated kinase
cancer stem cells
drug resistance
hepatocellular carcinoma
sorafenib
Medicina
Medicine
title_short Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
title_full Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
title_fullStr Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
title_full_unstemmed Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
title_sort Targeting AMP-activated kinase impacts hepatocellular cancer stem cells induced by long-term treatment with sorafenib
dc.creator.none.fl_str_mv Bort Bueno, Alicia Carmen|||0000-0003-1490-5823
Sánchez Gómez, Belén|||0000-0003-0971-1522
Mateos Gómez, Pedro Antonio|||0000-0002-5539-2289
Vara Ciruelos, Diana|||0000-0002-9508-2648
Rodríguez Henche, María de las Nieves|||0000-0001-9798-359X
Díaz-Laviada Marturet, Inés Cecilia|||0000-0001-9704-4373
author Bort Bueno, Alicia Carmen|||0000-0003-1490-5823
author_facet Bort Bueno, Alicia Carmen|||0000-0003-1490-5823
Sánchez Gómez, Belén|||0000-0003-0971-1522
Mateos Gómez, Pedro Antonio|||0000-0002-5539-2289
Vara Ciruelos, Diana|||0000-0002-9508-2648
Rodríguez Henche, María de las Nieves|||0000-0001-9798-359X
Díaz-Laviada Marturet, Inés Cecilia|||0000-0001-9704-4373
author_role author
author2 Sánchez Gómez, Belén|||0000-0003-0971-1522
Mateos Gómez, Pedro Antonio|||0000-0002-5539-2289
Vara Ciruelos, Diana|||0000-0002-9508-2648
Rodríguez Henche, María de las Nieves|||0000-0001-9798-359X
Díaz-Laviada Marturet, Inés Cecilia|||0000-0001-9704-4373
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv AMP-activated kinase
cancer stem cells
drug resistance
hepatocellular carcinoma
sorafenib
Medicina
Medicine
topic AMP-activated kinase
cancer stem cells
drug resistance
hepatocellular carcinoma
sorafenib
Medicina
Medicine
description Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells (CSCs) that self-renew and often escape therapy. The key metabolic sensor AMP-activated kinase (AMPK) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance (ALDH1A1, ABCB1A) and stem cell (CD133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib-induced cell death. We report that sorafenib-resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC, compared with the parental cells. Interestingly, AMPK knockdown with siRNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib-induced cell death. Conversely, the upregulation of AMPK, either by transfection or by pharmacological activation with A-769662, decreased the expression of ALDH1A1, ABCB1A, CD133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia-inducible factor HIF-1? as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem-like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-04-15
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10017/60095
https://dx.doi.org/10.1002/1878-0261.12488
url http://hdl.handle.net/10017/60095
https://dx.doi.org/10.1002/1878-0261.12488
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv FT Not available 2013-01
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:e_Buah Biblioteca Digital Universidad de Alcalá
instname:Universidad de Alcalá (UAH)
instname_str Universidad de Alcalá (UAH)
reponame_str e_Buah Biblioteca Digital Universidad de Alcalá
collection e_Buah Biblioteca Digital Universidad de Alcalá
repository.name.fl_str_mv
repository.mail.fl_str_mv
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