The proteomic landscape of ovarian cancer cells in response to melatonin

Cesário, Roberta Carvalho; Gaiotte, Letícia Barbosa; Cucielo, Maira Smaniotto; Silveira, Henrique Spaulonci; Santos, Lucilene Delazari dos; Zuccari, Débora Aparecida Pires de Campos; Seiva, Fábio Rodrigues Ferreira; Reíter, Russel J.; Chuffa, Luiz Gustavo de Almeida

doi:10.1016/j.lfs.2022.120352

Cited by 5 publications

(8 citation statements)

References 58 publications

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“…For this reason, melatonin has been proposed as an adjunct agent that can enhance cell survival and accelerate apoptotic phenomena in cell populations that are no longer viable. Melatonin is known to regulate redox status and promote inflammatory and immune response to various stimulants, through affinity receptors MT1 and MT2, which belong to the G-coupled protein receptor family [38]. The results of the current study revealed the existence of 53 additional proteins in the melatonin group, which can be divided into three major categories: immune and inflammatory response, cell cycle regulation and processes supporting protein and ion transportation.…”

Section: Discussionmentioning

confidence: 69%

“…Even under normal conditions, they appear to have opposed roles, where caspase 3 regulates apoptosis, whereas clusterin inhibits it [37]. The suppressing effects of heat stress were highlighted by the presence of cathepsin-D, a protease participating in the degradation of intracellular proteins [38]. Moreover, various stress sensors were found, including NmrA-like family domain-containing protein 1 [39], chloride intracellular channel protein 1 [40] and Parkinson disease protein 7 homolog [41].…”

Section: Discussionmentioning

confidence: 99%

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Proteomics Analysis of Pregnancy in Ewes under Heat Stress Conditions and Melatonin Administration

Bouroutzika,

Proikakis,

Theodosiadou

et al. 2024

Animals

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Melatonin is an indoleamine with broad spectrum properties that acts as a regulator of antioxidant and immune response in organisms. In our previous studies, melatonin improved redox status and inflammatory response in pregnant ewes under heat stress conditions. In the present study, using proteomics, the proteins regulated by melatonin during different stages of pregnancy and lambing were assessed. Twenty-two ewes equally divided into two groups, the melatonin (M) (n = 11) and control (C) group (n = 11), participated in the study and were exposed to heat stress during the first months of pregnancy. In the M group, melatonin implants were administered throughout pregnancy, every 40 days, until parturition (a total of four implants per ewe). Blood samples were collected at the beginning of the study simultaneously with the administration of the first melatonin implant (blood samples M1, C1), mating (M2, C2), second implant (M3, C3), fourth implant (M4, C4) and parturition (M5, C5), and MALDI-TOF analysis was performed. The results revealed the existence of 42 extra proteins in samples M2, M3 and M4 and 53 in M5 (sample at parturition) that are linked to melatonin. The biological processes of these proteins refer to boosted immune response, the alleviation of oxidative and endoplasmic reticulum stress, energy metabolism, the protection of the maternal organism and embryo development. This proteomics analysis indicates that melatonin regulates protective mechanisms and controls cell proliferation under exogenous or endogenous stressful stimuli during pregnancy and parturition.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of Pregnancy in Ewes under Heat Stress Conditions and Melatonin Administration

Bouroutzika,

Proikakis,

Theodosiadou

et al. 2024

Animals

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“…In addition, in the mitochondria, melatonin inhibits the PDK enzyme, which allows the conversion of pyruvate into acetyl-CoA, a component of the TCA cycle, causing a possible restoration of the normal metabolic phenotype of cells that use OXPHOS for energy generation [ 20 ]. Melatonin can also modulate several mitochondrial pathways in SKOV-3 cells and redirect cells to the oxidative mitochondrial phenotype, leading to a reversal of the malignant phenotype of cells [ 21 , 41 ]. These receptor-independent findings might be associated with other transport routes, such as involving GLUT1 and PEPT1/2.…”

Section: Discussionmentioning

confidence: 99%

“…Through the proteomic profile, Chuffa et al [ 48 ] showed overexpression of the beta subunit ATP synthase after melatonin treatment in a rat model of ovarian cancer. The ability of melatonin to alter the characteristics of the glycolytic metabolism of tumor cells has been recently reported, especially by upregulating proteins related to TCA cycle and ETC [ 41 ]. Our findings document a positive correlation between the enzyme-related genes responsible for melatonin synthesis and the alpha and beta subunits, corroborating other previous findings.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation

et al. 2022

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Ovarian cancer (OC) is the most lethal gynecologic malignancy, and melatonin has shown various antitumor properties. Herein, we investigated the influence of melatonin therapy on energy metabolism and mitochondrial integrity in SKOV-3 cells and tested whether its effects depended on MT1 receptor activation. SKOV-3 cells were exposed to different melatonin concentrations, and experimental groups were divided as to the presence of MT1 receptors (melatonin groups) or receptor absence by RNAi silencing (siRNA MT1+melatonin). Intracellular melatonin levels increased after treatment with melatonin independent of the MT1. The mitochondrial membrane potential of SKOV-3 cells decreased in the group treated with the highest melatonin concentration. Melatonin reduced cellular glucose consumption, while MT1 knockdown increased its consumption. Interconversion of lactate to pyruvate increased after treatment with melatonin and was remarkable in siRNA MT1 groups. Moreover, lactate dehydrogenase activity decreased with melatonin and increased after MT1 silencing at all concentrations. The UCSC XenaBrowser tool showed a positive correlation between the human ASMTL gene and the ATP synthase genes, succinate dehydrogenase gene (SDHD), and pyruvate dehydrogenase genes (PDHA and PDHB). We conclude that melatonin changes the glycolytic phenotype and mitochondrial integrity of SKOV-3 cells independent of the MT1 receptor, thus decreasing the survival advantage of OC cells.

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“…Thus, there is an unmet need for discovery of predictive biomarkers of extreme physiological variations in the age of female reproductive aging, while the same molecules could be targets for pharmacological treatment. The large amount of data generated in high throughput proteomic studies offers a source to comprehensively study differences in levels of circulating proteins associated with variation in age at menarche (AAM) and age at natural menopause (ANM), which individually, or as part of a network, can provide insight into the molecular mechanisms that affect timing of menarche and of natural menopause 3 , 4 . Circulating proteins in the blood have been a valuable source for biomarker discovery and drug target characterisation for various diseases 5 .…”

Section: Introductionmentioning

confidence: 99%

Mendelian randomization identifies circulating proteins as biomarkers for age at menarche and age at natural menopause

Yazdanpanah,

Jumentier,

Yazdanpanah

et al. 2024

Commun Biol

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Age at menarche (AAM) and age at natural menopause (ANM) are highly heritable traits and have been linked to various health outcomes. We aimed to identify circulating proteins associated with altered ANM and AAM using an unbiased two-sample Mendelian randomization (MR) and colocalization approach. By testing causal effects of 1,271 proteins on AAM, we identified 22 proteins causally associated with AAM in MR, among which 13 proteins (GCKR, FOXO3, SEMA3G, PATE4, AZGP1, NEGR1, LHB, DLK1, ANXA2, YWHAB, DNAJB12, RMDN1 and HPGDS) colocalized. Among 1,349 proteins tested for causal association with ANM using MR, we identified 19 causal proteins among which 7 proteins (CPNE1, TYMP, DNER, ADAMTS13, LCT, ARL and PLXNA1) colocalized. Follow-up pathway and gene enrichment analyses demonstrated links between AAM-related proteins and obesity and diabetes, and between AAM and ANM-related proteins and various types of cancer. In conclusion, we identified proteomic signatures of reproductive ageing in women, highlighting biological processes at both ends of the reproductive lifespan.

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The proteomic landscape of ovarian cancer cells in response to melatonin

Cited by 5 publications

References 58 publications

Proteomics Analysis of Pregnancy in Ewes under Heat Stress Conditions and Melatonin Administration

Proteomics Analysis of Pregnancy in Ewes under Heat Stress Conditions and Melatonin Administration

Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation

Mendelian randomization identifies circulating proteins as biomarkers for age at menarche and age at natural menopause

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