Displacement Pumps

The image is representative of three different experiments.


Depending on the physiopathological setting, autophagy has been proposed to protect from apoptosis, act as an apoptosis-alternative pathway to induce cell death or act together with apoptosis as a combined mechanism for cell death. Our observations are in line with previous results obtained in human glioma cells 13 and support the fact that stimulation of autophagy in response to cannabinoid treatment leads to apoptosis.

Nevertheless, further research is still necessary to clarify the precise mechanisms linking both cellular processes upon cannabinoid treatment. Stimulation of autophagy in many cellular settings relies on the inhibition of the mTORC1 complex, which have a central role in the control of protein synthesis, cell growth and cell proliferation through the regulation of several downstream targets. As a result of its central position in the control of cellular homeostasis, mTORC1 integrates signals from different inputs.

In this work, we found that cannabinoid treatment of HCC cells leads to Akt and mTORC1 inhibition, which is in agreement with our recent studies in glioma cells. These observations suggest that TRB3 and AMPK i are activated by different mechanisms in response to cannabinoid treatment, and ii regulate autophagy acting at different stages.

Two converging pathways have been described for AMPK regulation: A model of this mechanism of cannabinoid action in HCC cells is depicted in Figure 5. Moreover, knock down of the autophagic gene Atg5 as well as pharmacological inhibition of autophagy dramatically abolished the anti-tumoral activity of cannabinoids against subcutaneous HCC xenografts. Our data represent the first evidence for the antiproliferative action of cannabinoids in HCC cells in vivo and support that the ability of cannabinoids to inhibit mTORC1, stimulate AMPK and enhance autophagy could be therapeutically exploited for the management of HCC.

The anti-caspase-3 antibody and 3-MA were purchased to Sigma. All the other chemicals were obtained from Sigma. The human hepatoma cell line HuH-7 was kindly supply by Dr. One day before the experiments, the medium was changed to 0. Cells in logarithmic phase were cultured at a density of cells per cm 2 in a well plate. The 3-[4,5-dimethylthiazolyl-2] 2,5-diphenyl-tetrazolium bromide MTT cell viability assay was used to evaluate the effects of cannabinoids on cell growth and to determine the IC For each transfection, the following sequences were used: Each value was adjusted by using 18S RNA levels as a reference.

All animal studies were conducted in accordance with the Spanish institutional regulation for the housing, care and use of experimental animals and met the European Community directives regulating animal research. To study the in vivo antitumor activity of cannabinoids, hepatocarcinoma tumors were induced in athymic mice by subcutaneal injection or by liver implantation. Mice were then divided into different experimental groups of eight animals each, which received the following treatments as subcutaneous injections according to the experiment: The injection was repeated every day and treatment was continued for 15 days.

Tumor volumes were monitored every day using calliper measurements and were calculated by the formula: The body weight of the animals was recorded daily.

When tumor cells were implanted in the liver, the treatments were initiated 1 week after cells injection and administered intraperitoneally. Eight animals were used in each experimental group. At the end of the treatment, the animals were killed and xenografted tumors and livers weighted and frozen.

Differences were considered significant when the P -value was less than 0. Supplementary Information accompanies the paper on Cell Death and Differentiation website http: Edited by M Piacentini. This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue.

National Center for Biotechnology Information , U. Journal List Cell Death Differ v. Published online Apr 8. Author information Article notes Copyright and License information Disclaimer. This article has been corrected. See Cell Death Differ.

This article has been cited by other articles in PMC. Abstract Hepatocellular carcinoma HCC is the third cause of cancer-related death worldwide. Open in a separate window. Cell viability assay Cells in logarithmic phase were cultured at a density of cells per cm 2 in a well plate. In vivo studies To study the in vivo antitumor activity of cannabinoids, hepatocarcinoma tumors were induced in athymic mice by subcutaneal injection or by liver implantation.

Notes The authors declare no conflict of interest. Footnotes Supplementary Information accompanies the paper on Cell Death and Differentiation website http: Supplementary Material Supplementary Figure 1 Click here for additional data file. Supplementary Figure 2 Click here for additional data file.

Supplementary Figure 3 Click here for additional data file. Supplementary Figure Legends Click here for additional data file. Nat Rev Gastroenterol Hepatol. Expert Rev Gastroenterol Hepatol. The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Sorafenib in hepatocellular carcinoma. Br J Hosp Med Lond ; Developing better treatments in hepatocellular carcinoma.

Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. Selective autophagy in cancer development and therapy.

Autophagy in the liver. Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Role and regulation of autophagy in cancer. Autophagy in liver diseases. Prognostic significance of beclin 1-dependent apoptotic activity in hepatocellular carcinoma. Antimicrobial peptaibols, novel suppressors of tumor cells, targeted calcium-mediated apoptosis and autophagy in human hepatocellular carcinoma cells.

TRB3 links ER stress to autophagy in cannabinoid anti-tumoral action. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. Atg5 and Bcl-2 provide novel insights into the interplay between apoptosis and autophagy. Does autophagy have a license to kill mammalian cells. Lauren-Crist 2 0 54 1. Eva Lilienthal 1 0 70 1. Eva Lilienthal 2 0 71 0.

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