Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

Li, Mengling; Wu, Chengai; Muhammad, Jibran Sualeh; Yan, Dan; Tsuneyama, Koichi; Hatta, Hideki; Cui, Zheng‐Guo; Inadera, Hidekuni

doi:10.1016/j.redox.2020.101632

Cited by 37 publications

(25 citation statements)

References 55 publications

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“…As expected, both the apoptotic rate and G0/G1 cell cycle arrest were increased in cells that received combinatorial treatment of melatonin and thapsigargin via triggering ER stress. In fact, melatonin has been shown to exhibit more promising antitumour effect when combining with a wide range of drugs, including dabrafenib, 32 shikonin, 33 valproic acid 17 and cisplatin 34 . These evidences suggested that combinatorial treatment is an effective approach to enhance the capability of melatonin to combat cancer.…”

Section: Discussionmentioning

confidence: 99%

Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Huang

Yuan

Tang

et al. 2020

J Cellular Molecular Medi

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Melatonin exhibits antitumour activities in the treatment of many human cancers. In the present study, we aimed to improve the therapeutic potential of melatonin in gastric cancer. Our results confirmed that melatonin dose‐dependently suppressed the proliferation and necrosis, and increased G0/G1 phase arrest, apoptosis, autophagy and endoplasmic reticulum (ER) stress. The Ras‐Raf‐MAPK signalling pathway was activated in cells after melatonin treatment. RNA‐seq was performed and GSEA analysis further confirmed that many down‐regulated genes in melatonin‐treated cells were associated with proliferation. However, GSEA analysis also indicated that many pathways related to metastasis were increased after melatonin treatment. Subsequently, combinatorial treatment was conducted to further investigate the therapeutic outcomes of melatonin. A combination of melatonin and thapsigargin increased the apoptotic rate and G0/G1 cell cycle arrest when compared to treatment with melatonin alone. Melatonin in combination with thapsigargin triggered the increased expression of Bip, LC3‐II, phospho‐Erk1/2 and phospho‐p38 MAPK. In addition, STF‐083010, an IRE1a inhibitor, further exacerbated the decrease in survival rate induced by combinatorial treatment with melatonin and thapsigargin. Collectively, melatonin was effective in gastric cancer treatment by modifying ER stress.

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Section: Discussionmentioning

confidence: 99%

Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Huang

Yuan

Tang

et al. 2020

J Cellular Molecular Medi

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show abstract

“…There is a large amount of evidence on the benefits of melatonin in anticancer properties including its pro-apoptotic, anti-proliferative, anti-angiogenic, and anti-metastatic properties [ 11 , 12 , 13 ]. Melatonin also has a synergistic effect with different chemotherapeutic drugs [ 14 , 15 , 16 ]. In the clinical study, NSCLC patients concomitantly treated with melatonin exhibited better survival outcomes compared to those treated with chemotherapy alone [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin Downregulates PD-L1 Expression and Modulates Tumor Immunity in KRAS-Mutant Non-Small Cell Lung Cancer

Chao

Lee

et al. 2021

IJMS

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Non-small cell lung cancer (NSCLC) patients harboring a KRAS mutation have unfavorable therapeutic outcomes with chemotherapies, and the mutation also renders tolerance to immunotherapies. There is an unmet need for a new strategy for overcoming immunosuppression in KRAS-mutant NSCLC. The recently discovered role of melatonin demonstrates a wide spectrum of anticancer impacts; however, the effect of melatonin on modulating tumor immunity is largely unknown. In the present study, melatonin treatment significantly reduced cell viability accompanied by inducing cell apoptosis in KRAS-mutant NSCLC cell lines including A549, H460, and LLC1 cells. Mechanistically, we found that lung cancer cells harboring the KRAS mutation exhibited a higher level of programmed death ligand 1 (PD-L1). However, treatment with melatonin substantially downregulated PD-L1 expressions in both the presence and absence of interferon (IFN)-γ stimulation. Moreover, KRAS-mutant lung cancer cells exhibited higher Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) levels, and PD-L1 expression was positively correlated with YAP and TAZ in lung cancer cells. Treatment with melatonin effectively suppressed YAP and TAZ, which was accompanied by downregulation of YAP/TAZ downstream gene expressions. The combination of melatonin and an inhibitor of YAP/TAZ robustly decreased YAP and PD-L1 expressions. Clinical analysis using public databases revealed that PD-L1 expression was positively correlated with YAP and TAZ in patients with lung cancer, and PD-L1 overexpression suggested poor survival probability. An animal study further revealed that administration of melatonin significantly inhibited tumor growth and modulated tumor immunity in a syngeneic mouse model. Together, our data revealed a novel antitumor mechanism of melatonin in modulating the immunosuppressive tumor microenvironment by suppressing the YAP/PD-L1 axis and suggest the therapeutic potential of melatonin for treating NSCLC.

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“…Furthermore, melatonin-induced oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway in human histiocytic lymphoma (Li et al. 2020 ) plays a critical role in chronic Chagas disease by targeting the AMPK/NFE2L2/SIRT3 signalling pathway (Caballero et al. 2020 ).…”

Section: Introductionmentioning

confidence: 99%

SIRT 3 was involved in Lycium barbarum seed oil protection testis from oxidative stress: in vitro and in vivo analyses

Zhou

Wang

Zhao

et al. 2021

Pharmaceutical Biology

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Context Lycium barbarum L. (Solanaceae) seed oil (LBSO) exerts LBSO exerts protective effects in the testis in vivo and in vitro via upregulating SIRT3. Objective This study evaluates the effects and mechanism of LBSO in the d -galactose ( d -gal)-induced ageing testis. Materials and methods Male Sprague Dawley (SD) rats ( n = 30, 8-week-old) were randomly divided into three groups: LBSO group ( n = 10) where rats received subcutaneous injection of d -gal at 125 mg/kg/day for 8 weeks and intragastric administration of LBSO at 1000 mg/kg/day for 4 weeks, ageing model group ( n = 10) received 8-week-sunbcutaneous injection of d -gal, and control group ( n = 10) with same administration of normal saline. Lentivirus had established TM4 cells with SIRT3 overexpression or silencing before LBSO intervened in vitro . Results Treatment with LBSO, the levels of INHB and testosterone both increased, compared to ageing model. In vitro , we found the ED 50 of LBSO was 86.72 ± 1.49 and when the concentration of LBSO at 100 μg/mL to intervene TM4 cells, the number of cells increased from 8120 ± 676.2 to 15251 ± 1119, and the expression of SIRT3, HO-1, and SOD upregulated. However, HO-1 and SOD were dysregulated by silencing SIRT3. On the other hand, the expression of AMPK and PGC-1 α upregulated as an effect of SIRT3 overexpression by lentivirus, meanwhile the same increasing trend of that being found in cells treated with LBSO, compared to control group. Discussion and conclusions LBSO alleviated oxidative stress in d -gal-induced sub-acutely ageing testis and TM4 cells by suppressing the oxidative stress to mitochondria via SIRT3/AMPK/PGC-1α.

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Melatonin sensitises shikonin-induced cancer cell death mediated by oxidative stress via inhibition of the SIRT3/SOD2-AKT pathway

Cited by 37 publications

References 55 publications

Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Melatonin inhibiting the survival of human gastric cancer cells under ER stress involving autophagy and Ras‐Raf‐MAPK signalling

Melatonin Downregulates PD-L1 Expression and Modulates Tumor Immunity in KRAS-Mutant Non-Small Cell Lung Cancer

SIRT 3 was involved in Lycium barbarum seed oil protection testis from oxidative stress: in vitro and in vivo analyses

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