Melatonin suppresses lung cancer metastasis by inhibition of epithelial–mesenchymal transition through targeting to Twist

Chao, Chia Chia; Chen, Po Chun; Chiou, Pei Chen; Liu, Po I.; Yang, Yi; Reíter, Russel J.; Yang, Shun Fa; Tang, Chih Hsin

doi:10.1042/cs20180945

Cited by 44 publications

(42 citation statements)

References 53 publications

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“…We obtained Runx2 and osterix 3′-UTR DNA fragments from Invitrogen (Carlsbad, CA, USA) and subcloned them into the pmirGLO-control luciferase reporter vector (Promega, Madison, WI, USA). Luciferase activity was assayed using the method as described in our previous research [42,43].…”

Section: Methodsmentioning

confidence: 99%

CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts

Chen¹,

Liu²,

Fong

et al. 2019

IJMS

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CCN3, otherwise known as the nephroblastoma overexpressed (NOV) protein, is a cysteine-rich protein that belongs to the CCN family and regulates several cellular functions. Osteoblasts are major bone-forming cells that undergo proliferation, mineralization, renewal, and repair during the bone formation process. We have previously reported that CCN3 increases bone morphogenetic protein 4 (BMP-4) production and bone mineralization in osteoblasts, although the role of CCN3 remains unclear with regard to osteogenic transcription factors (runt-related transcription factor 2 (Runx2) and osterix). Here, we used alizarin red-S and alkaline phosphatase staining to show that CCN3 enhances osteoblast differentiation. Stimulation of osteoblasts with CCN3 increases expression of osteogenic factors such as BMPs, Runx2, and osterix. Moreover, we found that the inhibition of miR-608 expression is involved in the effects of CCN3 and that incubation of osteoblasts with CCN3 promotes focal adhesion kinase (FAK) and Akt phosphorylation. Our results indicate that CCN3 promotes the expression of Runx2 and osterix in osteoblasts by inhibiting miR-608 expression via the FAK and Akt signaling pathways.

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Section: Methodsmentioning

confidence: 99%

CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts

Chen¹,

Liu²,

Fong

et al. 2019

IJMS

Self Cite

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“…A 100 µL aliquot of cells prepared at a density of 1 × 10 5 cells/mL was plated in each of the 96 well plates. After 24 h, the culture medium was replaced with medium containing the IC 25…”

Section: Cell Culture and Exposure To Mlt And Pdnpsmentioning

confidence: 99%

Melatonin Enhances Palladium-Nanoparticle-Induced Cytotoxicity and Apoptosis in Human Lung Epithelial Adenocarcinoma Cells A549 and H1229

et al. 2020

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Palladium nanoparticles (PdNPs) are increasingly being used in medical and biological applications due to their unique physical and chemical properties. Recent evidence suggests that these nanoparticles can act as both a pro-oxidant and as an antioxidant. Melatonin (MLT), which also shows pro- and antioxidant properties, can enhance the efficacy of chemotherapeutic agents when combined with anticancer drugs. Nevertheless, studies regarding the molecular mechanisms underlying the anticancer effects of PdNPs and MLT in cancer cells are still lacking. Therefore, we aimed to investigate the potential toxicological and molecular mechanisms of PdNPs, MLT, and the combination of PdNPs with MLT in A549 lung epithelial adenocarcinoma cells. We evaluated cell viability, cell proliferation, cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis in cells treated with different concentrations of PdNPs and MLT. PdNPs and MLT induced cytotoxicity, which was confirmed by leakage of lactate dehydrogenase, increased intracellular protease, and reduced membrane integrity. Oxidative stress increased the levels of reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), protein carbonyl content (PCC), lipid hydroperoxide (LHP), and 8-isoprostane. Combining PdNPs with MLT elevated the levels of mitochondrial dysfunction by decreasing mitochondrial membrane potential (MMP), ATP content, mitochondrial number, and expression levels of the main regulators of mitochondrial biogenesis. Additionally, PdNPs and MLT induced apoptosis and oxidative DNA damage due to accumulation of 4-hydroxynonenal (HNE), 8-oxo-2′-deoxyguanosine (8-OhdG), and 8-hydroxyguanosine (8-OHG). Finally, PdNPs and MLT increased mitochondrially mediated stress and apoptosis, which was confirmed by the increased expression levels of apoptotic genes. To our knowledge, this is the first study demonstrating the effects of combining PdNPs and MLT in human lung cancer cells. These findings provide valuable insights into the molecular mechanisms involved in PdNP- and MLT-induced toxicity, and it may be that this combination therapy could be a potential effective therapeutic approach. This combination effect provides information to support the clinical evaluation of PdNPs and MLT as a suitable agents for lung cancer treatment, and the combined effect provides therapeutic value, as non-toxic concentrations of PdNPs and MLT are more effective, better tolerated, and show less adverse effects. Finally, this study suggests that MLT could be used as a supplement in nano-mediated combination therapies used to treat lung cancer.

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“…12 The indoleamine has great pharmacological promise as an antioxidant enzyme that can scavenge free radicals, and protect from oxidative damage. 13,14 Previous studies has shown that melatonin can inhibit the proliferation of various human cancers, including leukemia, 15,16 hepatocarcinoma, 17 breast cancer, 18 colorectal cancer, 19,20 lung cancer, 21,22 and gastric carcinoma. 23,24 However, studies investigating the molecular link between the UPR and autophagy activation by melatonin in GC are sparse.…”

Section: Introductionmentioning

confidence: 99%

<p>The Therapeutic Effect of Melatonin on GC by Inducing Cell Apoptosis and Autophagy Induced by Endoplasmic Reticulum Stress</p>

Zheng¹,

Tu²,

Wang³

et al. 2019

OTT

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Background: Gastric cancer (GC) is the main malignancy affecting a large population worldwide. Lack of effective enough treatment is one of the leading factors contributing to the high mortality rate. Melatonin, a naturally occurring compound, has been proven to exert cytotoxic and antiproliferative effects on human gastric cancers. Nevertheless, the mechanisms of anti-gastric cancer of melatonin remain elucidated. It is believed that endoplasmic reticulum (ER) stress and its resultant unfolded protein response (UPR) are connected to the survival, progression, and chemoresistance of various tumor cells via multiple cellular procedures, such as autophagy. In this study, the effects of melatonin on human gastric cancer cell lines AGS and SGC-7901 was assessed to reveal the interaction between melatonin, endoplasmic reticulum stress, and autophagy in gastric cancer. Methods: CCK-8, the wound healing analysis, colony formation assay, immunofluorescence analysis, Western blotting, flow cytometry, and animal models were used in the current study. Results: The data demonstrated that melatonin could inhibit GC growth, proliferation, and invasion both in vivo and in vitro. Apoptosis and autophagy induced in a concentrationdependent manner is response to melatonin-induced ER stress. Melatonin induced the expression of apoptotic and autophagy-related proteins, which was markedly attenuated by the ER stress inhibitor 4-PBA and autophagy inhibitor 3-MA. In addition, we used the specific IRE1 inhibitor STF 083010, finding that inhibiting IRE1 could considerably relieve ER stress-induced autophagy activity, as revealed by the reduction of LC3-II and Beclin-1. Conclusion: This study confirmed that melatonin-induced inhibition of GC cell proliferation is mediated by the activation of the IRE/JNK/Beclin1 signaling.

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Melatonin suppresses lung cancer metastasis by inhibition of epithelial–mesenchymal transition through targeting to Twist

Cited by 44 publications

References 53 publications

CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts

CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts

Melatonin Enhances Palladium-Nanoparticle-Induced Cytotoxicity and Apoptosis in Human Lung Epithelial Adenocarcinoma Cells A549 and H1229

<p>The Therapeutic Effect of Melatonin on GC by Inducing Cell Apoptosis and Autophagy Induced by Endoplasmic Reticulum Stress</p>

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