Melatonin Represses Metastasis in<i>Her2</i>-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

Mao, Lulu; Summers, Whitney M.; Xiang, Shulin; Yuan, Lin; Dauchy, Robert T.; Reynolds, Amberly; Wren-Dail, Melissa A; Pointer, David T.; Frasch, Tripp; Blask, David E.; Hill, Steven M.

doi:10.1158/1541-7786.mcr-16-0158

Cited by 56 publications

(56 citation statements)

References 45 publications

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“…Regulation of ERK1/2 activity by melatonin has been reported to play important roles in the proliferation, migration, and differentiation of a variety of cell types, including neurons, immune, stem and cancer cells, and protective effects in diseases like multiple sclerosis (Álvarez‐Sánchez et al; Farez et al), cancer development (Mao et al), and atherosclerosis (Cheng et al). However, little is known about the respective role of the two melatonin receptors, MT 1 and MT 2 , and the signaling pathway(s) involved.…”

Section: Discussionmentioning

confidence: 99%

Melatonin MT₁ and MT₂ receptor ERK signaling is differentially dependent on G_i/o and G_q/11 proteins

Chen

Cecon

Karamitri

et al. 2020

Journal of Pineal Research

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G protein‐coupled receptors (GPCRs) transmit extracellular signals into cells by activating G protein‐ and β‐arrestin‐dependent pathways. Extracellular signal‐regulated kinases (ERKs) play a central role in integrating these different linear inputs coming from a variety of GPCRs to regulate cellular functions. Here, we investigated human melatonin MT1 and MT2 receptors signaling through the ERK1/2 cascade by employing different biochemical techniques together with pharmacological inhibitors and siRNA molecules. We show that ERK1/2 activation by both receptors is exclusively G protein‐dependent, without any participation of β‐arrestin1/2 in HEK293 cells. ERK1/2 activation by MT1 is only mediated though Gi/o proteins, while MT2 is dependent on the cooperative activation of Gi/o and Gq/11 proteins. In the absence of Gq/11 proteins, however, MT2‐induced ERK1/2 activation switches to a β‐arrestin1/2‐dependent mode. The signaling cascade downstream of G proteins is the same for both receptors and involves activation of the PI3K/PKCζ/c‐Raf/MEK/ERK cascade. The differential G protein dependency of MT1‐ and MT2‐mediated ERK activation was confirmed at the level of EGR1 and FOS gene expression, two ERK1/2 target genes. Gi/o/Gq/11 cooperativity was also observed in Neuroscreen‐1 cells expressing endogenous MT2, whereas in the mouse retina, where MT2 is engaged into MT1/MT2 heterodimers, ERK1/2 signaling is exclusively Gi/o‐dependent. Collectively, our data reveal differential signaling modes of MT1 and MT2 in terms of ERK1/2 activation, with an unexpected Gi/o/Gq/11 cooperativity exclusively for MT2. The plasticity of ERK activation by MT2 is highlighted by the switch to a β‐arrestin1/2‐dependent mode in the absence of Gq/11 proteins and by the switch to a Gi/o mode when engaged into MT1/MT2 heterodimers, revealing a new mechanism underlying tissue‐specific responses to melatonin.

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Section: Discussionmentioning

confidence: 99%

Melatonin MT₁ and MT₂ receptor ERK signaling is differentially dependent on G_i/o and G_q/11 proteins

Chen

Cecon

Karamitri

et al. 2020

Journal of Pineal Research

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“…The principal EMT molecular features include loss of the epithelial marker E-cadherin, and overexpression of mesenchymal markers N-cadherin and vimentin [78,79]. Various studies also indicate that melatonin has anti-invasive and anti-metastatic effects, which involve multiple cellular processes including EMT [80][81][82].…”

Section: Effect Of Melatonin In Epithelial Mesenchymal Transition Marmentioning

confidence: 99%

The impact of melatonin and carbon ion irradiation on cancer stem cells

Liu¹,

Reíter²

2017

Nucl Med Biomed Imaging

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Aim: Cancer stem cells (CSCs) exhibited an excessive migratory and invasive potential. Melatonin may inhibit multiple crucial signals associated with tumor stem cell self-renewal, viability, invasiveness, tumor growth, and therapy resistance. Carbon ion irradiation may be a promising therapeutic modality in both non-stem-like and stem-like tumor cells in contrast to photon irradiation. A comprehensive understanding of the mechanisms and molecular pathways associated with invasive properties of CSCs is essential in developing novel treatment options for cancer therapy that target CSCs. Materials and methods:A systematic review of the existing literature was conducted using the following search terms: 'melatonin', 'X-ray irradiation', 'charged particle irradiation', 'carbon ion irradiation', 'cancer stem cells', 'tumor-initiating cells' and 'cancer stem-like cells'. The search used PubMed and spanned the period from January 2000 to December 2016. Conclusion:Cancer stem cells possess the capacity of self-renewal and pluripotency, generating all cells within a tumor, and are responsible for tumor growth, therapy resistance and metastasis. Melatonin attenuated AKT activation, EZH2 S21 phosphorylation, EZH2-STAT3 interactions and altered histone modifications to reduce tumor initiation and propagation of brain tumor stem cells (BTSC). Melatonin increases the efficacy of chemotherapeutic agents, targeting both the tumor bulk and BTSCs through the regulation of the expression and function of the ABCG2/BCRP transporter by inducing the methylation of its promoter. Melatonin treatment induced cell death with ultrastructural characteristics of autophagy. Breast cancer stem cells (BCSCs) are responsive to melatonin treatment by way of reducing the viability and the invasiveness of breast cancer mammospheres as well as regulating the expression of OCT4, N-cadherin and vimentin proteins associated with epithelial mesenchymal transition in BCSCs. Carbon irradiation is effective in brain tumor stem cell (BTSC) elimination with relative biologic effectiveness (RBE) in the range of 1.87-3.44. Carbon ion irradiation may be a promising therapeutic modality because it reduces migration and invasion processes in both head and neck squamous cell carcinoma and cancer stem cells in contrast to photon irradiation. Low LET X-ray irradiation may essentially eradicate the non-stem-like tumor cells, consequently the radioresistant cancer stem-like cell population is obviously enriched. In contrast, carbon ion irradiation may eradicate both non-stemlike and stem-like tumor cells at the same time. Carbon ion irradiation is a promising tool to eradicate putative colon cancer stem-like cells. Further investigation to elucidate the mechanisms and molecular pathways involved in cancer stem cells particularly associated with melatonin and carbon ion irradiation certainly is warranted.

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“…Melatonin has also been shown to exert antiproliferative and cytotoxic effects on human cancers, including colorectal cancer [7], neuroblastoma [8], hepatocarcinoma [9], lung cancer [10-12], breast cancer [13], prostate cancer [14, 15], and leukaemia [16, 17]. In a gastric cancer cell line it was already shown that proapoptotic effect of melatonin could be due to activation of a Caspase-dependent pathway and inhibition of the nuclear translocation of NF-κB p65, two processes that are regulated by p38 and c-Jun N-terminal kinase (JNK) [18].…”

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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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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Melatonin Represses Metastasis inHer2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

Cited by 56 publications

References 45 publications

Melatonin MT₁ and MT₂ receptor ERK signaling is differentially dependent on G_i/o and G_q/11 proteins

Melatonin MT₁ and MT₂ receptor ERK signaling is differentially dependent on G_i/o and G_q/11 proteins

The impact of melatonin and carbon ion irradiation on cancer stem cells

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

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Melatonin Represses Metastasis inHer2-Postive Human Breast Cancer Cells by Suppressing RSK2 Expression

Cited by 56 publications

References 45 publications

Melatonin MT1 and MT2 receptor ERK signaling is differentially dependent on Gi/o and Gq/11 proteins

Melatonin MT1 and MT2 receptor ERK signaling is differentially dependent on Gi/o and Gq/11 proteins

The impact of melatonin and carbon ion irradiation on cancer stem cells

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

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Product

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Melatonin MT₁ and MT₂ receptor ERK signaling is differentially dependent on G_i/o and G_q/11 proteins

Melatonin MT₁ and MT₂ receptor ERK signaling is differentially dependent on G_i/o and G_q/11 proteins