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] |