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

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.

Melatonin-Induced Changes in Cytosolic Calcium Might be Responsible for Apoptosis Induction in Tumour Cells

“…We have shown that in tumour cells, melatonin is able to induce ER stress and activate the apoptotic process. This observation was already made in rats with diethylnitrosamine-induced hepatocarcinogenesis [20]. However, ER stress markers were not elevated in non-tumour EA.hy926 cells.…”

“…Melatonin acts cooperatively with ER stress to promote the apoptosis of cancer cells or inhibits ER stress to attenuate chemotherapy-associated side effects and chemoresistance. In rats with diethylnitrosamine-induced hepatocarcinogenesis, melatonin treatment significantly increases the expression of activating transcription factor 6 (ATF6), C/EBP homologous protein (CHOP), and binding immunoglobulin protein (BIP), which might further promote the incidence of apoptosis [20]. Apoptosis derived from unresolved ER stress has also been observed, indicating that a sustained ER stress response could contribute to tumour cell death [21].…”

Melatonin for the prevention and treatment of cancer

“…Another study suggested that melatonin attenuated hepatocarcinogenesis induced by diethylnitrosamine in rats, by activating ER stress and inducing apoptosis [133]. …”

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

“…It enhances the expression of the ERS proteins ATF6 and CHOP, improves survival rates, and successfully attenuates liver injury [24]. Furthermore, melatonin treatment alleviates ERS during bleomycin-induced pulmonary fibrosis [25].…”