Melatonin reverses tunicamycin‐induced endoplasmic reticulum stress in human hepatocellular carcinoma cells and improves cytotoxic response to doxorubicin by increasing CHOP and decreasing Survivin

Abstract

Chemoresistance in hepatocellular carcinoma (HCC) is associated with multiple cellular responses to environmental stresses, such as nutrient deprivation and hypoxia. Nevertheless, whether ER stress resulting from nutrient deprivation and tumor hypoxia contributes to drug resistance remains unclear. Melatonin increased the efficacy of chemotherapeutic drugs in hepatocellular carcinoma in our previous studies. However, the effects of melatonin on endoplasmic reticulum (ER) stress-induced resistance to chemotherapeutic agents in HCC have not been tested. The effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells against doxorubicin was investigated in this study. Pretreatment of HepG2 and SMMC-7721 cells (two human hepatocellular carcinoma cell lines) with tunicamycin, an ER stress inducer, drastically decreased the rate of apoptosis generated by doxorubicin. Interestingly, co-pretreatment with tunicamycin and melatonin significantly increased apoptosis induced by doxorubicin. Simultaneously, the expression of phosphorylated AKT (p-AKT) was elevated in HepG2 and SMMC-7721 cells given tunicamycin but reduced in the presence of melatonin. Furthermore, consistent with inhibition of AKT activation by using the PI3K inhibitor LY294002, melatonin elevated the levels of CHOP (C/EBP-homologous protein) and reduced the levels of Survivin (a member of the inhibitor of apoptosis protein family)suggesting that inhibition of the PI3K/AKT pathway by melatonin-reversed ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells. These results demonstrate that melatonin attenuates ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by down-regulating the PI3K/AKT pathway, increasing the levels of CHOP and decreasing the levels of Survivin.

Melatonin modifies cellular stress in the liver of septic mice by reducing reactive oxygen species and increasing the unfolded protein response

“…Particularly the PERK-mediated signaling pathway seems to be influenced, e.g. the transcriptional downregulation or reduced activation of PERK, EIF2α, ATF4, CHOP and GADD34 was detected by different researchers (Fan et al, 2013;Ji et al, 2012;Tunon et al, 2013;Wang et al, 2011;Zaouali et al, 2013).…”

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

“…It has been documented that melatonin modulates the signalling of neuronal cell death [47] and bladder cancer cells induced by ERS [48]. Melatonin significantly reverses tunicamycin-induced ERS in human hepatocellular carcinoma cells and improves cytotoxic responses to doxorubicin by increasing the expression of CHOP [49]. A couple of studies revealed that melatonin alleviates Cd-induced cellular stress and germ cell apoptosis in testes [50] and prevents bisphenol A-induced apoptosis by controlling BCL2 expression and ameliorating oxidative stress in the testes and sperm [51].…”

Effects of Melatonin on Liver Injuries and Diseases

“…The mechanism of cooperative apoptosis induction might be related to reduced Bcl-2 expression and improved Bax and caspase3 expression [176]. Previous studies have shown that melatonin elevated the effects of some chemotherapeutic drugs in HCC [177]. A study identified the roles of melatonin in ER stress-induced resistance to chemotherapeutic agents in HCC.…”