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Table 1 A comprehensive list of signaling pathways involved in the anticancer effects of melatonin and their molecular mechanism of action

From: Interactions of melatonin with various signaling pathways: implications for cancer therapy

Signaling pathway effected

Cell line

Melatonin dose/concentration

Major effect on carcinogenesis

Other findings

Refs.

IGF signaling pathway

Prostate cancer (PCa) cell line (LNCaP)

Reduced cancer cell proliferation

Upregulation of IGFBP3 and downregulation of IGF1R

[142]

VEGF signaling pathway

MDA-MB-231 and MCF-7 cell lines

1 mM and 1 ng/mL

Suppression of cancer cell growth and viability

Decrease in VEGF-A protein expression and increase in IGFBP-3, IGFPB-6, IGF-1, IGF-1R proteins

[143]

MDA-MB-468 cells

0.01 mM, 0.1 mM and 1 mM

Suppression of angiogenetic features of breast cancer cells

Inhibition of expression of IGF-IR, HIF-1α and VEGF proteins through regulation of miRNA-152-3p

[144]

Notch signaling pathway

Glioblastoma cell lines (U251 and T98G)

100 µM and 1 mM

Inhibition of viability and self-renewal of glioblastoma stem-like cells (GSCs)

EZH2-Notch1 signaling pathway suppression

[98]

MCF-7 breast cancer cells

100 µM

Inhibition of growth and viability of breast cancer cells

Altered conductance through Ca2+ and voltage-activated K+ (BK) channels and disruption of Notch1 signaling pathway

[99]

Endometriotic eutopic epithelial cells (EEC) from patients’ tissues

1 mM

Suppression of 17β-estradiol-induced invasion, migration and epithelial to mesenchymal transition (EMT) of endometriotic cells

Decrease in the activity of the Notch signaling

[100]

GC-1 spg cell line

0.1 µM

Growth inhibition of testicular germ cell tumor

Suppression of tumor growth through regulation of miRNA

[101]

NF-κB signaling pathway

HUVEC

10 µM

Inhibition of angiogenesis

Decrease in the production of MMP9 via inhibition of NF-κB signaling

[116]

HepG2 cells

1 mM

Upregulation of NF-κB pathway proteins

[117]

MDA-MB-231 cell line xenograft in Balb/c nude athymic mice

40 mg/Kg

Decrease in tumor size and growth

Decrease in expression of NF-κB pathway

[117]

Human vulvar‐derived steroid independent leiomyosarcoma SK‐LMS‐1 cells xenograft in athymic, inbred nude rats

75 μg

Suppression of aerobic glycolysis (Warburg effect), survival and tumor growth

Suppression of activation of ERK1/2, AKT, GSK3β and NF-kB (p65)

[31]

Warburg Effect

Ewing sarcoma

CL: A-673, TC-71 and A-4573

0,1 mM incubation for 2,4,6,8 h

Reversal in metabolic profile

Increased glucose uptake, LDH activity, lactate production and HIF-1α activation / Not effective on chondrosarcoma cells

[175]

Warburg Effect,

Suppressed phospho-activation of ERK 1/2, AKT, GSK3β and NF-kB (p65)

Leiomyosarcoma

CL: SK-LMS-1

100 nM–1 pM incubation for 6 days

Repressed cell proliferation and cell invasion

Suppressed aerobic glycolysis, complete inhibition of tumor linoleic acid uptake, 13-HODE release, as well as significant reductions in tumor cAMP levels, DNA content and [(3) H]-thymidine incorporation into DNA

[31]

mTORC1/ribosomal protein S6 kinase beta-1 (p70S6K)/ribosomal protein S6 (RP-S6) pathway

Hepatocellular carcinoma

CL: Hep3B

2 mM

Preventing HIF-1α synthesis to block the cytoprotective mitophagy induced by the hypoxic microenvironment, reduced resistance to sorafenib

Enhanced Akt phosphorylation by the mTORC1/C2 negative feedback

[34]

mTOR/Akt

Hepatoma H22

10 & 20 mg/kg

Melatonin triggers an autophagic process by enhancing Beclin 1 expression and inducing a conversion of microtubule-associated protein 1 light chain 3(LC3)-I to LC3-II

The autophagy inhibitor, 3-methyladenine(3-MA), significantly enhanced the melatonin-induced apoptosis in mouse hepatoma H22 cells

[35]

mTOR/Akt

Head and neck SCC

CL: Cal-27 and SCC-9

0.1, 0.5 or 1 mmol/L melatonin combined with 20 nM rapamycin

Decreased cell viability, proliferation and clonogenic capacity, increased ROS production, increasing apoptosis and mitophagy

Bined treatment with rapamycin and melatonin blocked the negative feedback loop from the specific downstream effector of mTOR activation S6K1 to Akt signalling

[37]

ERK1/2 and p38 MAP kinases

Hepatoma cells H4IIE

0–5.0 mM

Inhibit the effects of H2O2-induced oxidative stress

Attenuated H2O2‐induced activation of the ERK1/2 and p38 MAP kinases

[45]

PI3K/Akt/mTOR pathway

Melanoma cell B16F10

0–1.0 mM

Reduced cell viability

Cell viability was significantly decreased after treatment with melatonin combined with ER stress from thapsigargin or tunicamycin compared to no treatment or treatment with melatonin only

[46]

RTK/PKC/Akt/NF-kappaB pathway

C6 glioma cells

Intraperitoneal administration of 15 mg/kg

Inhibition of cell growth

Increase of basal redox state

[48]

p38 MAPK

Breast cancer

CL: MCF-7/6, MCF-7/Her2.1, and MCF-7/CXCR4 cells

1 nM

Suppression of the invasive potential

Repressed the proteinase activity of MMP-2 and MMP-9

[62]

Akt/ GSK3β

Breast cancer

MCF-7, MCF-7/ steroid receptor negative

Circadian cycle of plasma melatonin level was assessed

Suppression of EMT

 

[63]

MAPK/JNK

Prostate cancer

LNCaP

0–3 mM incubation for 0–48 h

Apoptosis

Melatonin-induced apoptosis was JNK- and p38-dependent, but ERK-independent

[65]

MAPKs/ERK/JNK

HepG2 human hepatocarcinoma cells

1 and 2.5 mM

Cell viability

Both melatonin concentrations increased the expression of phosphorylated p38, ERK, and JNK. ERK activation was completely abolished in the presence of luzindole

[66]

JNK/MAPK

Lung cancer

A549

0.1–5 mM incubation for 24 h

Cell migration was reduced to about 20%

The expression level of OPN, MLCK and phosphorylation of MLC of A549 cells were reduced, while the expression of occludin was conversely elevated, and occludin located on the cell surface was obviously increased. The phosphorylation status of JNK in A549 cells was also reduced when cells were treated by melatonin

[67]

P38 MAPK

Human melanoma SK-MEL-1 cells

0–1 mM incubation for 24–72 h

Decreases cell proliferation and induces melanogenesis

Comparative studies with known antioxidants such as N-acetyl-l-cysteine and trolox indicate that the growth of SK-MEL-1 cells is highly sensitive to antioxidants

[68]

P38 MAPK/JNK/ERK

Gastric cancer cell line (AGS)

0,1,2 mM incubation for 0–72 h

Apoptosis, enhancing the anti-tumour effects of cisplatin, with low systemic toxicity

Increased caspase-3 cleavage and Bax protein expression and decreased Bcl-2 protein expression in a time-dependent manner

[69]

P38 MAPK/Akt/ERK/JNK

RCC cells (Caki-1 and Achn)

0.5–2 mm

Reducing metastasis potential

Inhibition of MMP-9

[176]

JNK/SP-1 signaling

Nasopharyngeal carcinoma

0,0.5,1.0 mM

Suppression of the motility of NPC

Regulating TPA-induced MMP-9 gene expression via inhibiting SP-1-DNA binding ability, the c-Jun N-terminal kinase/mitogen-activated protein kinase pathway is involved in the melatonin-mediated tumor suppressor activity

[70]

Rho-associated protein kinase (ROCK)

MCF-7 cells

1 nm

Reduces migration and invasiveness

Increased expression of two cell surface adhesion proteins, E-cadherin and beta(1)-integrin, inhibitory effects on cell migration by changing cytoskeletal organization of leader MCF-7 cells

[72]

Wnt pathway and Raf/MEK/ERK pathway

UC3 bladder cancer cells

Cotreatment with melatonin 1 µM and VPA 5 mM incubation for 24 h

Apoptosis, autophagy and necrosis

Increased the expression of endoplasmic reticulum (ER)-stress-related genes, enhanced the expression of E-cadherin, and decreased the expression of N-cadherin, Fibronectin, Snail and Slug

[84]

miRNAs

MCF-7 human breast cancer cells

1 and 100 nM

22 miRNAs were differentially expressed in melatonin-treated MCF-7 cells depending on the concentration of melatonin treated with

[158]

miRNAs

PC-3 prostate cancer cells

1 mM incubation for 4 h under hypoxia

33 miRNAs (> 2 folds) including miRNA3195 and miRNA 374b were significantly upregulated and 16 miRNAs were downregulated in melatonin-treated PC-3 cells under hypoxia compared to untreated control

upregulation of miRNA3195 and miRNA374b mediates anti-angiogenic property

Melatonin significantly attenuated the expression of hypoxia-inducible factor (HIF)-1 alpha, HIF-2 alpha and vascular endothelial growth factor (VEGF) at mRNA level in hypoxic PC-3 cells melatonin enhanced the expression of miRNA3195 and miRNA 374b in hypoxic PC-3 cells

[159]

miRNAs

HCT 116 and MCF-7 cells

Incubation for 0–72 h, concentration not mentioned clearly

Decrease in miR-24 levels post-transcriptionally affecting cell proliferation, DNA damage, RNA metabolism and cell shape and transformation

miR-24 is upregulated in colon, breast and head and neck datasets and its levels negatively correlate with overall survival

[160]

miRNAs

Human glioma cell lines U87, U373 and U251

100 μM, 1 μM and 1 nM

Promoting cell apoptosis and repressing cell proliferation, migration and invasion

Downregulating the expression of miR-155 via repression of c-MYB

[161]

miRNA

Gastric cancer

0,1,5 µM incubation for 0–72 h

Apoptosis, enhancing the expression of miR-16-5p

miR-16-5p targeted Smad3 and consequently negatively regulated the abundance of Smad3

[162]