Melatonin Activates Endoplasmic Reticulum Stress and Apoptosis in Rats with Diethylnitrosamine-Induced Hepatocarcinogenesis.

Andrea Janz Moreira,Carlos Thadeu Cerski,Raquel Ordoñez,Jaqueline Nascimento Picada,Jose L. Mauriz,Norma Possa Marroni,Andrés García-Palomo,Javier González-Gallego,Matias A Avila

doi:10.1371/journal.pone.0144517

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide because of its high incidence, its metastatic potential and the low efficacy of conventional treatment. Inactivation of apoptosis is implicated in tumour progression and chemotherapy resistance, and has been linked to the presence of endoplasmic reticulum stress. Melatonin, the main product of the pineal gland, exerts anti-proliferative, pro-apoptotic and anti-angiogenic effects in HCC cells, but these effects still need to be confirmed in animal models. Male Wistar rats in treatment groups received diethylnitrosamine (DEN) 50 mg/kg intraperitoneally twice/once a week for 18 weeks. Melatonin was given in drinking water at 1 mg/kg/d, beginning 5 or 12 weeks after the start of DEN administration. Melatonin improved survival rates and successfully attenuated liver injury, as shown by histopathology, decreased levels of serum transaminases and reduced expression of placental glutathione S-transferase. Furthermore, melatonin treatment resulted in a significant increase of caspase 3, 8 and 9 activities, polyadenosine diphosphate (ADP) ribose polymerase (PARP) cleavage, and Bcl-associated X protein (Bax)/Bcl-2 ratio. Cytochrome c, p53 and Fas-L protein concentration were also significantly enhanced by melatonin. Melatonin induced an increased expression of activating transcription factor 6 (ATF6), C/EBP-homologous protein (CHOP) and immunoglobulin heavy chain-binding protein (BiP), while cyclooxygenase (COX)-2 expression decreased. Data obtained suggest that induction of apoptosis and ER stress contribute to the beneficial effects of melatonin in rats with DEN-induced HCC.

Highlights

Hepatocellular carcinoma (HCC) is the fifth most common disease in men worldwide, the seventh in women and the third leading cause of cancer-related mortality
Significant differences between means were evaluated by one-way analysis of variance; in the case of significance, the means were compared with the Bonferroni test
Due to the fact that melatonin activates the extrinsic pathway of apoptosis in HepG2 cells [17], we evaluated the activity of caspase 8, a key initiator caspase that mediates the death receptor pathway of apoptosis, in which the binding of Fas to Fas ligand (Fas-L) induces receptor clustering and formation of death-induced signalling complexes

Summary

Introduction

Hepatocellular carcinoma (HCC) is the fifth most common disease in men worldwide, the seventh in women and the third leading cause of cancer-related mortality. It has been established as the final step for chronic liver diseases, and it is closely related to fibrosis and cirrhosis with a variable aetiology [1]. In developed countries (North America, Europe and Japan) infection with hepatitis C virus (HCV) and alcohol use are the main risk factors. In underdeveloped countries HCC is associated with in hepatitis B (HBV) and exposure to aflatoxin B1 [3]. The late diagnosis and the low efficacy of drugs employed in its treatment make HCC the third cause of cancer death. It is well known that HCC develops resistance to chemotherapeutic agents, which complicates HCC management [1]

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