Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation

Bu, Lijia; Yu, Han; Fan, Lulu; Li, Xiaoqiu; Wang, Fang; Liu, Jiatao; Zhong, Fei; Zhang, Congjun; Wei, Wei; Wang, Hua; Sun, Guoping

doi:10.3748/wjg.v23.i6.986

Cited by 50 publications

(46 citation statements)

References 40 publications

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“…The ability of melatonin to induce apoptosis has already been described in cancer cells, e.g. hepatoma cells [24], but also, to a limited extent, in non-tumour cells.…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis is one of the main mechanisms implicated in cell death, and its inactivation contributes to tumour progression and chemotherapy resistance [22]. Proapoptotic effects of melatonin [23, 24], and its effects in combination with ER stress inducers (e.g. tunicamycin) have been reported in different hepatocellular carcinoma cell lines [25].…”

Section: Introductionmentioning

confidence: 99%

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

Chovancova

Hudecová

Lencesova

et al. 2017

Cell Physiol Biochem

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Background/Aims: Melatonin is a hormone transferring information about duration of darkness to the organism and is known to modulate several signaling pathways in the cells, e.g. generation of endoplasmic reticulum stress, oxidative status of the cells, etc. Melatonin has been shown to exert antiproliferative and cytotoxic effects on various human cancers. We proposed that this hormone can differently affect tumour cells and healthy cells. Methods: We compared the effect of 24 h melatonin treatment on calcium transport (by fluorescent probes FLUO-3AM and Rhod-5N), ER stress (determined as changes in the expression of CHOP, XBP1 and fluorescently, using Thioflavin T), ROS formation (by CellROX® Green/Orange Reagent) and apoptosis induction (by Annexin-V-FLUOS/propidiumiodide) in two tumour cell lines – ovarian cancer cell line A2780 and stable cell line DLD1 derived from colorectal carcinoma, with non-tumour endothelial cell line EA.hy926. Results: Melatonin increased apoptosis in both tumour cell lines more than twice, while in EA.hy926 cells the apoptosis was increased only by 30%. As determined by silencing with appropriate siRNAs, both, type 1 sodium/calcium exchanger and type 1 IP₃ receptor are involved in the apoptosis induction. Antioxidant properties of melatonin were significantly increased in EA.hy926 cells, while in tumour cell lines this effect was much weaker. Conclusion: Taken together, melatonin has different antioxidative effects on tumour cells compared to non-tumour ones; it also differs in the ability to induce apoptosis through the type 1 sodium/calcium exchanger, and type 1 IP₃ receptor. Different targeting of calcium transport systems in tumour and normal, non-tumour cells is suggested as a key mechanism how melatonin can exert its anticancer effects. Therefore, it might have a potential as a novel therapeutic implication in cancer treatment.

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“…The ability of melatonin to induce apoptosis has already been described in cancer cells, e.g. hepatoma cells [24], but also, to a limited extent, in non-tumour cells.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Chovancova

Hudecová

Lencesova

et al. 2017

Cell Physiol Biochem

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“…Similar to 4BPA, melatonin is able to protect against cerebral IR injury through inhibiting ERS via PERK and IRE1 signals [57]. Downregulation of ATF-6 by melatonin contributes to ERS-induced apoptosis of human hepatoma cells [58]. In the current study, we found that melatonin could abrogate busulfan-induced ERS in mouse SSCs by inhibiting the ERS-related genes IRE1 and PERK, which further depressed pro-apoptotic transcript CHOP activation, then inhibited P53 expression and resulted in the reduction of PUMA, and consequently decreased the accumulation of cellular caspase, thereby preventing cell apoptosis (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Cui

Ren

et al. 2017

Cell Physiol Biochem

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Background/Aims: Busulfan is commonly used for cancer chemotherapy. Although it has the advantage of increasing the survival rate of patients, it can cause male infertility via damaging the testes and reducing sperm counts. Therefore, the underlying mechanism should be explored, and new agents should be developed to protect the male reproductive system from busulfan-induced damage. Endoplasmic reticulum stress (ERS) is considered a key contributor to numerous pathologies. Despite several studies linking ERS to toxicants, studies have yet to determine whether ERS is a contributing factor to busulfan-induced testicular damage. Melatonin is a well-known broad-spectrum antioxidant, anti-inflammatory and antitumour agent, but the effects of melatonin on busulfan-induced ERS in mouse testes damage are less documented. Methods: The effects of melatonin were measured by immunofluorescence staining, Western blot, qRT-PCR analysis and flow cytometry assay. The underlying mechanism was investigated by measuring ERS. Results: We found that ERS was strongly activated in mouse testes (in vivo) and the C18-4 cell line (in vitro) after busulfan administration. ERS-related apoptosis proteins such as caspase-12, CHOP and caspase-3 were activated, and the expression of apoptotic proteins such as P53 and PUMA were upregulated. Furthermore, we investigated whether melatonin reduced the extent of damage to mouse testes and improved the survival rates of busulfan-treated mice. When exploring the underlying mechanisms, we found melatonin could counteract ERS by decreasing the expression levels of the ERS markers GRP78, ATF6, pIRE1 and XBP1 in mouse testes and mouse SSCs (C18-4 cells). Moreover, it blocked the activation of ERS-related apoptosis proteins caspase-12, CHOP and caspase-3 and suppressed P53 and PUMA expression stimulated by busulfan both in vivo and in vitro. Conclusion: Our results demonstrate that ERS is an important mediator for busulfan-induced apoptosis. The attenuation of ERS by melatonin can prevent busulfan-treated SSCs apoptosis and protect busulfan-treated testes from damage. Thus, this study suggests that melatonin may alleviate the side effects of busulfan for male patients during clinical treatment.

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“…Melatonin‐mediated inhibition of autophagy (Ordoñez et al, ) and/or activation of caspase‐3 (Martín‐Renedo et al, ) accounts for induction of Poly ADP‐ribose polymerase (PARP)‐1cleavage in the cells. Melatonin suppresses cancer cell survival through inhibition of cyclooxygenase‐2 (COX‐2) and its viability‐related factors (Bu et al, ; Carbajo‐Pescador, Steinmetz, et al, ; Fan, Sun, et al, ; Fan, Sun, Ma, Zhong, & Wei, ; Zhang, ). Melatonin induces activation of p53 and p21 (Martín‐Renedo et al, ).…”

Section: Introductionmentioning

confidence: 99%

Human hepatocellular carcinoma: Protection by melatonin

Mortezaee

2018

Journal Cellular Physiology

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Despite great scientific breakthroughs toward understanding the identity of human hepatocellular carcinoma (HCC) mechanistically, there are still no clinically efficient therapeutic methods for this cancer. Melatonin (N-acetyl-5-methoxytryptamine) is a multi-tasking hormone that has long been known for its anti-cancer activity against various human cancers including HCC, which is a focus of this review. PubMed database was searched for relevant articles with the keywords: hepatocellular carcinoma (HCC), melatonin, apoptosis, proliferation, invasion, angiogenesis, autophagy, oxidative stress, tumor immunity, and mitogen-activated protein kinase (MAPK) focusing on just human cell lines and English language articles. Melatonin inhibits apoptosis resistance and activates both extrinsic and intrinsic pathways of apoptosis in HCC. Melatonin induces ensoplasmic reticulum (ER)- and autophagy-mediated apoptosis in cancer cells. Melatonin works against cancer cell proliferation, motility, and invasiveness by modulating actions of a variety of transcription factors and related pathways. Melatonin also relieves an immunosuppressive state in HCC cancer cells through making a control over tumor-derived exosomes. Both pro-and anti-oxidative functions of melatonin are necessary for combating HCC. Combination of melatonin with chemotherapy could also provide cumulative effects on cancer cells. Melatonin exerts most of these roles by acting on the members of MAPK family.

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Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation

Cited by 50 publications

References 40 publications

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

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

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

Human hepatocellular carcinoma: Protection by melatonin

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