Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways
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 proli...
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| Autores principales: | , , , , , |
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| Formato: | Articulo Preprint |
| Lenguaje: | Inglés |
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2018
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| Acceso en línea: | http://sedici.unlp.edu.ar/handle/10915/104731 http://hdl.handle.net/11336/96536 |
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I19-R120-10915-104731 |
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dspace |
| institution |
Universidad Nacional de La Plata |
| institution_str |
I-19 |
| repository_str |
R-120 |
| collection |
SEDICI (UNLP) |
| language |
Inglés |
| topic |
Bioquímica Biología Akt/mTOR Apoptosis Cell cycle arrest Hepatocellular carcinoma cells Linalool Ras/MAPKs Reactive oxygen species |
| spellingShingle |
Bioquímica Biología Akt/mTOR Apoptosis Cell cycle arrest Hepatocellular carcinoma cells Linalool Ras/MAPKs Reactive oxygen species Rodenak Kladniew, Boris Emilio Castro, María Agustina Stärkel, Peter De Saeger, Christine García de Bravo, Margarita María Crespo, Rosana Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways |
| topic_facet |
Bioquímica Biología Akt/mTOR Apoptosis Cell cycle arrest Hepatocellular carcinoma cells Linalool Ras/MAPKs Reactive oxygen species |
| 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. |
| format |
Articulo Preprint |
| author |
Rodenak Kladniew, Boris Emilio Castro, María Agustina Stärkel, Peter De Saeger, Christine García de Bravo, Margarita María Crespo, Rosana |
| author_facet |
Rodenak Kladniew, Boris Emilio Castro, María Agustina Stärkel, Peter De Saeger, Christine García de Bravo, Margarita María Crespo, Rosana |
| author_sort |
Rodenak Kladniew, Boris Emilio |
| title |
Linalool induces cell cycle arrest and apoptosis in HepG2 cells through oxidative stress generation and modulation of Ras/MAPK and Akt/mTOR pathways |
| 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 |
| publishDate |
2018 |
| url |
http://sedici.unlp.edu.ar/handle/10915/104731 http://hdl.handle.net/11336/96536 |
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