Transcriptional and post‐translational regulation of Bim controls apoptosis in melatonin‐treated human renal cancer Caki cells

Park, Eun Jung; Woo, Seon Min; Min, Kyoung‐jin; Kwon, Taeg Kyu

doi:10.1111/jpi.12102

Cited by 41 publications

(43 citation statements)

References 47 publications

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“…Melatonin is also reported to influence (increase) p21 in various cells . This would be consistent with the hypothesis that melatonin acts like a proteasome inhibitor . Melatonin has also been reported to inhibit cyclin D1 expression in MCF‐7 breast cancer cells and in human esteoblastic cells .…”

Section: Melatonin the Circadian Clock And Cell Cyclesupporting

confidence: 81%

“…The possibility that melatonin has molecular actions within cells that do not require traditional receptors has been considered, particularly with regard to melatonin's free radical‐scavenging activities . While there is no direct evidence that melatonin directly inhibits proteasomes in the SCN or PT, there is recent experimental evidence that melatonin inhibits proteasomes of renal cancer cells . Vriend and Reiter reviewed the many similarities of melatonin and the proteasome inhibitor bortezomib, on signal transduction.…”

Section: Melatonin and The Proteasomementioning

confidence: 99%

“…The data of Park et al. suggest that at least in renal cancer cells, melatonin can inhibit the proteasome directly.…”

Section: Melatonin and The Proteasomementioning

confidence: 99%

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Melatonin feedback on clock genes: a theory involving the proteasome

Vriend

Reíter

2014

Journal of Pineal Research

212

159

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The expression of 'clock' genes occurs in all tissues, but especially in the suprachiasmatic nuclei (SCN) of the hypothalamus, groups of neurons in the brain that regulate circadian rhythms. Melatonin is secreted by the pineal gland in a circadian manner as influenced by the SCN. There is also considerable evidence that melatonin, in turn, acts on the SCN directly influencing the circadian 'clock' mechanisms. The most direct route by which melatonin could reach the SCN would be via the cerebrospinal fluid of the third ventricle. Melatonin could also reach the pars tuberalis (PT) of the pituitary, another melatonin-sensitive tissue, via this route. The major 'clock' genes include the period genes, Per1 and Per2, the cryptochrome genes, Cry1 and Cry2, the clock (circadian locomotor output cycles kaput) gene, and the Bmal1 (aryl hydrocarbon receptor nuclear translocator-like) gene. Clock and Bmal1 heterodimers act on E-box components of the promoters of the Per and Cry genes to stimulate transcription. A negative feedback loop between the cryptochrome proteins and the nucleus allows the Cry and Per proteins to regulate their own transcription. A cycle of ubiquitination and deubiquitination controls the levels of CRY protein degraded by the proteasome and, hence, the amount of protein available for feedback. Thus, it provides a post-translational component to the circadian clock mechanism. BMAL1 also stimulates transcription of REV-ERBa and, in turn, is also partially regulated by negative feedback by REV-ERBa. In the 'black widow' model of transcription, proteasomes destroy transcription factors that are needed only for a particular period of time. In the model proposed herein, the interaction of melatonin and the proteasome is required to adjust the SCN clock to changes in the environmental photoperiod. In particular, we predict that melatonin inhibition of the proteasome interferes with negative feedback loops (CRY/PER and REV-ERBa) on Bmal1 transcription genes in both the SCN and PT. Melatonin inhibition of the proteasome would also tend to stabilize BMAL1 protein itself in the SCN, particularly at night when melatonin is naturally elevated. Melatonin inhibition of the proteasome could account for the effects of melatonin on circadian rhythms associated with molecular timing genes. The interaction of melatonin with the proteasome in the hypothalamus also provides a model for explaining the dramatic 'time of day' effect of melatonin injections on reproductive status of seasonal breeders. Finally, the model predicts that a proteasome inhibitor such as bortezomib would modify circadian rhythms in a manner similar to melatonin.

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Section: Melatonin the Circadian Clock And Cell Cyclesupporting

confidence: 81%

Section: Melatonin and The Proteasomementioning

confidence: 99%

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Melatonin feedback on clock genes: a theory involving the proteasome

Vriend

Reíter

2014

Journal of Pineal Research

212

159

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“…Moreover, clinical sample analysis found a higher survival rate in MTNR1A high /MMP-9 low patients than in MTNR1A low /MMP-9 high patients [135]. Melatonin also induced apoptosis by upregulating the expression of Bim in renal cancer Caki cells, at both transcriptional level and post-translational level [136]. Furthermore, co-treatment of melatonin (1 mM) and thapsigargin (50 nM) induced more apoptosis in human renal cancer cells than treatment with thapsigargin alone, which was through ROS-mediated upregulation of CCAAT-enhancer-binding protein homologous protein [137].…”

Section: Experimental Studiesmentioning

confidence: 99%

Melatonin for the prevention and treatment of cancer

et al. 2017

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The epidemiological studies have indicated a possible oncostatic property of melatonin on different types of tumors. Besides, experimental studies have documented that melatonin could exert growth inhibition on some human tumor cells in vitro and in animal models. The underlying mechanisms include antioxidant activity, modulation of melatonin receptors MT1 and MT2, stimulation of apoptosis, regulation of pro-survival signaling and tumor metabolism, inhibition on angiogenesis, metastasis, and induction of epigenetic alteration. Melatonin could also be utilized as adjuvant of cancer therapies, through reinforcing the therapeutic effects and reducing the side effects of chemotherapies or radiation. Melatonin could be an excellent candidate for the prevention and treatment of several cancers, such as breast cancer, prostate cancer, gastric cancer and colorectal cancer. This review summarized the anticancer efficacy of melatonin, based on the results of epidemiological,experimental and clinical studies, and special attention was paid to the mechanisms of action.

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“…On the other hand, melatonin induces Bim expression [61]. Bim interacts with other Bcl-2 proteins to antagonize their anti-apoptotic activities, leading to apoptosis.…”

Section: Activation Of Intrinsic and Extrinsic Apoptotic Pathwaysmentioning

confidence: 99%