Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways

Autores
Rodenak Kladniew, Boris Emilio; Castro, Maria Agustina; Stärkel, Peter; De Saeger, Christine; Garcia, Margarita Maria; Crespo, Rosana
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Aims Linalool is a plant-derived monoterpene with anticancer activity, however its mechanisms of action remain poorly understood. The aim of this work was to elucidate the anticancer mechanisms of action of linalool in hepatocellular carcinoma (HCC) HepG2 cells. Main methods Cell viability and proliferation were determined by WST-1 assay and BrdU incorporation, respectively. Cell cycle analysis was assessed through flow cytometry (FC) and western blot (WB). Apoptosis was determined by caspase-3 activity, TUNEL assay and WB. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by FC and fluorescence microscopy. Expression of Ras, MAPKs (ERK, JNK and p38) and Akt/mTOR pathways were evaluated by WB. Key findings Linalool (0–2.5 mM) dose-dependently inhibited cell proliferation by inducing G0/G1 cell cycle arrest, through Cdk4 and cyclin A downregulation, p21 and p27 upregulation, and apoptosis, characterized by MMP loss, caspase-3 activation, PARP cleavage and DNA fragmentation. Low concentrations of linalool (1.0 mM) reduced membrane-bound Ras and Akt activity whereas higher amounts (2.0 mM) triggered mTOR inhibition and ROS generation, in correlation with MAPKs activation and Akt phosphorylation. ROS scavenger N-acetyl-L-cysteine partially rescued HepG2 cell growth and prevented MPP depolarization, ERK and JNK activation. Moreover, specific ERK and Akt phosphorylation inhibitors potentiated linalool anti-cancer activity, pointing Akt and ERK activation as pro-survival mechanisms in response to higher concentrations of linalool. Significance This report reveals that linalool induces G0/G1 arrest and apoptosis in HepG2 cells involving Ras, MAPKs and Akt/mTOR pathways and suggests that linalool is a promising anticancer agent for HCC therapy.
Fil: Rodenak Kladniew, Boris Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Castro, Maria Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Stärkel, Peter. Université Catholique de Louvain; Bélgica. Cliniques Universitaires Saint-Luc; Bélgica
Fil: De Saeger, Christine. Université Catholique de Louvain; Bélgica
Fil: Garcia, Margarita Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Crespo, Rosana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Materia
AKT/MTOR
APOPTOSIS
CELL CYCLE ARREST
HEPATOCELLULAR CARCINOMA CELLS
LINALOOL
RAS/MAPKS
REACTIVE OXYGEN SPECIES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/96536
Acceder
id CONICETDig_acd215963d3f74bc634dd1738bfe88fa
oai_identifier_str oai:ri.conicet.gov.ar:11336/96536
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathwaysRodenak Kladniew, Boris EmilioCastro, Maria AgustinaStärkel, PeterDe Saeger, ChristineGarcia, Margarita MariaCrespo, RosanaAKT/MTORAPOPTOSISCELL CYCLE ARRESTHEPATOCELLULAR CARCINOMA CELLSLINALOOLRAS/MAPKSREACTIVE OXYGEN SPECIEShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Aims Linalool is a plant-derived monoterpene with anticancer activity, however its mechanisms of action remain poorly understood. The aim of this work was to elucidate the anticancer mechanisms of action of linalool in hepatocellular carcinoma (HCC) HepG2 cells. Main methods Cell viability and proliferation were determined by WST-1 assay and BrdU incorporation, respectively. Cell cycle analysis was assessed through flow cytometry (FC) and western blot (WB). Apoptosis was determined by caspase-3 activity, TUNEL assay and WB. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by FC and fluorescence microscopy. Expression of Ras, MAPKs (ERK, JNK and p38) and Akt/mTOR pathways were evaluated by WB. Key findings Linalool (0–2.5 mM) dose-dependently inhibited cell proliferation by inducing G0/G1 cell cycle arrest, through Cdk4 and cyclin A downregulation, p21 and p27 upregulation, and apoptosis, characterized by MMP loss, caspase-3 activation, PARP cleavage and DNA fragmentation. Low concentrations of linalool (1.0 mM) reduced membrane-bound Ras and Akt activity whereas higher amounts (2.0 mM) triggered mTOR inhibition and ROS generation, in correlation with MAPKs activation and Akt phosphorylation. ROS scavenger N-acetyl-L-cysteine partially rescued HepG2 cell growth and prevented MPP depolarization, ERK and JNK activation. Moreover, specific ERK and Akt phosphorylation inhibitors potentiated linalool anti-cancer activity, pointing Akt and ERK activation as pro-survival mechanisms in response to higher concentrations of linalool. Significance This report reveals that linalool induces G0/G1 arrest and apoptosis in HepG2 cells involving Ras, MAPKs and Akt/mTOR pathways and suggests that linalool is a promising anticancer agent for HCC therapy.Fil: Rodenak Kladniew, Boris Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Castro, Maria Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Stärkel, Peter. Université Catholique de Louvain; Bélgica. Cliniques Universitaires Saint-Luc; BélgicaFil: De Saeger, Christine. Université Catholique de Louvain; BélgicaFil: Garcia, Margarita Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Crespo, Rosana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaPergamon-Elsevier Science Ltd2018-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/96536Rodenak Kladniew, Boris Emilio; Castro, Maria Agustina; Stärkel, Peter; De Saeger, Christine; Garcia, Margarita Maria; et al.; Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways; Pergamon-Elsevier Science Ltd; Life Sciences; 199; 4-2018; 48-590024-3205CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0024320518301048info:eu-repo/semantics/altIdentifier/doi/10.1016/j.lfs.2018.03.006info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-11-12T09:41:15Zoai:ri.conicet.gov.ar:11336/96536instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-11-12 09:41:15.658CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
title Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
spellingShingle Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
Rodenak Kladniew, Boris Emilio
AKT/MTOR
APOPTOSIS
CELL CYCLE ARREST
HEPATOCELLULAR CARCINOMA CELLS
LINALOOL
RAS/MAPKS
REACTIVE OXYGEN SPECIES
title_short Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
title_full Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
title_fullStr Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
title_full_unstemmed Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
title_sort Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
dc.creator.none.fl_str_mv Rodenak Kladniew, Boris Emilio
Castro, Maria Agustina
Stärkel, Peter
De Saeger, Christine
Garcia, Margarita Maria
Crespo, Rosana
author Rodenak Kladniew, Boris Emilio
author_facet Rodenak Kladniew, Boris Emilio
Castro, Maria Agustina
Stärkel, Peter
De Saeger, Christine
Garcia, Margarita Maria
Crespo, Rosana
author_role author
author2 Castro, Maria Agustina
Stärkel, Peter
De Saeger, Christine
Garcia, Margarita Maria
Crespo, Rosana
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv AKT/MTOR
APOPTOSIS
CELL CYCLE ARREST
HEPATOCELLULAR CARCINOMA CELLS
LINALOOL
RAS/MAPKS
REACTIVE OXYGEN SPECIES
topic AKT/MTOR
APOPTOSIS
CELL CYCLE ARREST
HEPATOCELLULAR CARCINOMA CELLS
LINALOOL
RAS/MAPKS
REACTIVE OXYGEN SPECIES
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Aims Linalool is a plant-derived monoterpene with anticancer activity, however its mechanisms of action remain poorly understood. The aim of this work was to elucidate the anticancer mechanisms of action of linalool in hepatocellular carcinoma (HCC) HepG2 cells. Main methods Cell viability and proliferation were determined by WST-1 assay and BrdU incorporation, respectively. Cell cycle analysis was assessed through flow cytometry (FC) and western blot (WB). Apoptosis was determined by caspase-3 activity, TUNEL assay and WB. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by FC and fluorescence microscopy. Expression of Ras, MAPKs (ERK, JNK and p38) and Akt/mTOR pathways were evaluated by WB. Key findings Linalool (0–2.5 mM) dose-dependently inhibited cell proliferation by inducing G0/G1 cell cycle arrest, through Cdk4 and cyclin A downregulation, p21 and p27 upregulation, and apoptosis, characterized by MMP loss, caspase-3 activation, PARP cleavage and DNA fragmentation. Low concentrations of linalool (1.0 mM) reduced membrane-bound Ras and Akt activity whereas higher amounts (2.0 mM) triggered mTOR inhibition and ROS generation, in correlation with MAPKs activation and Akt phosphorylation. ROS scavenger N-acetyl-L-cysteine partially rescued HepG2 cell growth and prevented MPP depolarization, ERK and JNK activation. Moreover, specific ERK and Akt phosphorylation inhibitors potentiated linalool anti-cancer activity, pointing Akt and ERK activation as pro-survival mechanisms in response to higher concentrations of linalool. Significance This report reveals that linalool induces G0/G1 arrest and apoptosis in HepG2 cells involving Ras, MAPKs and Akt/mTOR pathways and suggests that linalool is a promising anticancer agent for HCC therapy.
Fil: Rodenak Kladniew, Boris Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Castro, Maria Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Stärkel, Peter. Université Catholique de Louvain; Bélgica. Cliniques Universitaires Saint-Luc; Bélgica
Fil: De Saeger, Christine. Université Catholique de Louvain; Bélgica
Fil: Garcia, Margarita Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Crespo, Rosana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
description Aims Linalool is a plant-derived monoterpene with anticancer activity, however its mechanisms of action remain poorly understood. The aim of this work was to elucidate the anticancer mechanisms of action of linalool in hepatocellular carcinoma (HCC) HepG2 cells. Main methods Cell viability and proliferation were determined by WST-1 assay and BrdU incorporation, respectively. Cell cycle analysis was assessed through flow cytometry (FC) and western blot (WB). Apoptosis was determined by caspase-3 activity, TUNEL assay and WB. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by FC and fluorescence microscopy. Expression of Ras, MAPKs (ERK, JNK and p38) and Akt/mTOR pathways were evaluated by WB. Key findings Linalool (0–2.5 mM) dose-dependently inhibited cell proliferation by inducing G0/G1 cell cycle arrest, through Cdk4 and cyclin A downregulation, p21 and p27 upregulation, and apoptosis, characterized by MMP loss, caspase-3 activation, PARP cleavage and DNA fragmentation. Low concentrations of linalool (1.0 mM) reduced membrane-bound Ras and Akt activity whereas higher amounts (2.0 mM) triggered mTOR inhibition and ROS generation, in correlation with MAPKs activation and Akt phosphorylation. ROS scavenger N-acetyl-L-cysteine partially rescued HepG2 cell growth and prevented MPP depolarization, ERK and JNK activation. Moreover, specific ERK and Akt phosphorylation inhibitors potentiated linalool anti-cancer activity, pointing Akt and ERK activation as pro-survival mechanisms in response to higher concentrations of linalool. Significance This report reveals that linalool induces G0/G1 arrest and apoptosis in HepG2 cells involving Ras, MAPKs and Akt/mTOR pathways and suggests that linalool is a promising anticancer agent for HCC therapy.
publishDate 2018
dc.date.none.fl_str_mv 2018-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/96536
Rodenak Kladniew, Boris Emilio; Castro, Maria Agustina; Stärkel, Peter; De Saeger, Christine; Garcia, Margarita Maria; et al.; Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways; Pergamon-Elsevier Science Ltd; Life Sciences; 199; 4-2018; 48-59
0024-3205
CONICET Digital
CONICET
url http://hdl.handle.net/11336/96536
identifier_str_mv Rodenak Kladniew, Boris Emilio; Castro, Maria Agustina; Stärkel, Peter; De Saeger, Christine; Garcia, Margarita Maria; et al.; Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways; Pergamon-Elsevier Science Ltd; Life Sciences; 199; 4-2018; 48-59
0024-3205
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0024320518301048
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.lfs.2018.03.006
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
publisher.none.fl_str_mv Pergamon-Elsevier Science Ltd
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.24909

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