Blockage of melatonin receptors impairs p53-mediated prevention of DNA damage accumulation

Santoro, Raffaela; Mori, Federica; Marani, Marina; Grasso, Giuseppe; Cambria, Maria Anna; Blandino, Giovanni; Muti, Paola; Strano, Sabrina

doi:10.1093/carcin/bgt025

Cited by 52 publications

(52 citation statements)

References 57 publications

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“…P53 further accumulates in the nucleus and activates the DNA repair process 41 . Melatonin is known to induce phosphorylation of p53 at Ser-15 42, 43 , thus activating p53. We tested the ability of melatonin and its metabolites to induce p53 phosphorylation at Ser-15 as a response to UVB damage in comparison to melatonin.…”

Section: Resultsmentioning

confidence: 99%

Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways

Janjetovic

Jarrett

Lee

et al. 2017

Sci Rep

133

174

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Ultraviolet light (UV) is an inducer of reactive oxygen species (ROS) as well as 6-4-photoproducts and cyclobutane pyrimidine dimers (CPD) in the skin, which further cause damage to the skin cells. Irradiation of cultured human melanocytes with UVB stimulated ROS production, which was reduced in cells treated with melatonin or its metabolites: 6-hydroxymelatonin (6-OHM), N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), N-acetylserotonin (NAS), and 5-methoxytryptamine (5-MT). Melatonin and its derivatives also stimulated the expression of NRF2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) and its target enzymes and proteins that play an important role in cell protection from different damaging factors including UVB. Silencing of NRF2 using siRNA diminished the protective effects of melatonin, while the membrane melatonin receptors (MT1 or MT2) did not change the activities of either melatonin or its derivatives. Melatonin and its metabolites enhanced the DNA repair in melanocytes exposed to UVB and stimulated expression of p53 phosphorylated at Ser-15. In conclusion, melatonin and its metabolites protect melanocytes from UVB-induced DNA damage and oxidative stress through activation of NRF2-dependent pathways; these actions are independent of an effect on the classic membrane melatonin receptors. Thus, melatonin and its derivatives can serve as excellent protectors of melanocytes against UVB-induced pathology.

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Section: Resultsmentioning

confidence: 99%

Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways

Janjetovic

Jarrett

Lee

et al. 2017

Sci Rep

133

174

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“…The most important phosphorylation sites on p53 are Ser-15 which promotes accumulation and activation of p53 and DNA repair, and Ser-46 which regulates apoptosis following DNA damage [10]. Previously it was shown that hormonal factors such as melatonin can induce the p53-dependent DNA damage response through stimulation of phosphorylation at Ser-15 but not at Ser-46 [56, 76, 77]. …”

Section: Resultsmentioning

confidence: 99%

Novel non-calcemic secosteroids that are produced by human epidermal keratinocytes protect against solar radiation

Slominski

Janjetovic

Kim

et al. 2015

The Journal of Steroid Biochemistry and Molecular Biology

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CYP11A1 hydroxylates the side chain of vitamin D3 (D3) in a sequential fashion [D3→20S(OH)D3→20,23(OH)2D3→ 17,20,23(OH)3D3], in an alternative to the classical pathway of activation [D3→25(OH)D3→1,25(OH)2D3]. The products/intermediates of the pathway can be further modified by the action of CYP27B1. The CYP11A1-derived products are biologically active with functions determined by the lineage of the target cells. This pathway can operate in epidermal keratinocytes. To further define the role of these novel secosteroids we tested them for protective effects against UVB-induced damage in human epidermal keratinocytes, melanocytes and HaCaT keratinocytes, cultured in vitro. The secosteroids attenuated ROS, H2O2 and NO production by UVB-irradiated keratinocytes and melanocytes, with an efficacy similar to 1,25(OH)2D3, while 25(OH)D3 had lower efficacy. These attenuations were also seen to some extent for the 20(OH)D3 precursor, 20S-hydroxy-7-dehydrocholesterol. These effects were accompanied by upregulation of genes encoding enzymes responsible for defence against oxidative stress. Using immunofluorescent staining we observed that the secosteroids reduced the generation cyclobutane pyrimidine dimers in response to UVB and enhanced expression of p53 phosphorylated at Ser-15, but not at Ser-46. Additional evidence for protection against DNA damage in cells exposed to UVB and treated with secosteroids was provided by the Comet assay where DNA fragmentation was markedly reduced by 20(OH)D3 and 20,23(OH)2D3. In conclusion, novel secosteroids that can be produced by the action of CYP11A1 in epidermal keratinocytes have protective effects against UVB radiation.

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“…In the majority of these reports, melatonin acted via the MT1 membrane receptor to thwart breast cancer cell proliferation. A single report [205] claimed that both the MT1 and MT2 receptors were required for melatonin to prevent p53-mediated DNA damage. Other actions of melatonin that are likely related to the capacity of melatonin to hinder mitotic activity of mammary cancer cells includes its ability to arrest the cell cycle in the G1 phase [206], to curb aromatase activity [207], to keep in check aerobic glycolysis (Warburg effect) and to restrain the uptake of the n -6 fat, linoleic acid (LA), a growth factor for breast cancer cells [208].…”

Section: Melatonin and Cancer Progressionmentioning

confidence: 99%

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis

Reíter

Rosales-Corral

Tan

et al. 2017

IJMS

358

357

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There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin’s co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.

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Blockage of melatonin receptors impairs p53-mediated prevention of DNA damage accumulation

Cited by 52 publications

References 57 publications

Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways

Melatonin and its metabolites protect human melanocytes against UVB-induced damage: Involvement of NRF2-mediated pathways

Novel non-calcemic secosteroids that are produced by human epidermal keratinocytes protect against solar radiation

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis

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