Melatonin inhibits human melanoma cells proliferation and invasion via cell cycle arrest and cytoskeleton remodeling

Abstract

Among skin cancers,
 melanoma has the highest mortality rate. The heterogeneous genetic melanoma
 background leads to a tumor-propagating capacity particularly important in
 maintaining therapeutic resistance, and tumor recurrence. The identification of
 efficient molecules able to control melanoma progress represents an important
 opportunity for new therapeutic strategies, particularly in combination with the
 current standard-of-care treatments. In this context,
 several studies have reported the antitumor effects of melatonin against
 different types of cancer, including melanoma. Here,
 we describe the underlying mechanisms associated with melatonin’s activity in
 human melanoma cell lines, focusing on cell cycle and cytoskeleton
 remodeling. Interestingly, while melatonin induced melanocyte
 DNA replication, melanoma cells exhibited cell cycle arrest in the G1-phase.
 This phenomenon was associated with cyclin-D1 downregulation or p21
 overexpression. The efficacy of melatonin on melanoma cells survival and
 proliferation was detected using the clonogenic assay, with a decrease in both
 the number and size of colonies. Additionally, melatonin induced a dramatic
 cytoskeleton remodeling in all melanoma cell lines, leading to a star-like
 morphology or cell swelling. The role of melatonin on melanoma cytoskeleton was
 associated with the actin disruption, with thinning and/or broken actin fibers,
 and weak and/or loss of paxillin along stress fibers. These data support the
 observed findings that melatonin impairs melanoma invasion in skin
 reconstructed models. Together, our results suggest that melatonin could be
 used to control melanoma growth and support basic and
 clinical studies on melatonin as a promising immunometabolic
 adjuvant for melanoma therapy.

Melatonin as a Repurposed Drug for Melanoma Treatment

“…It possesses various functions ranging from regulating circadian rhythms to antioxidant, anti-inflammatory, immunomodulatory, and anti-aging properties. Importantly, it also exerts cytoprotective effects in normal cells and triggers apoptotic signals in oncogenic cells [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. As melatonin is lipophilic in nature, it can easily penetrate through the cellular membrane to protect intracellular structures such as DNA and mitochondria from oxidative stress induced by free radical generation.…”

“…Melatonin also activates the apoptosis-targeting proteins p53 and p21. [ 33 , 34 , 35 , 38 , 45 ]. Apart from causing apoptosis, melatonin and its metabolites act as antioxidants forming a free radical scavenger cascade protecting tissues from oxidative damage.…”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…It is not surprising that the migration of metastatic melanoma, which is dependent on acidic pH e , is promoted by the prion protein [ 67 , 484 , 485 ]. Experimental studies on skin reconstructed with melanoma cell lines found treatment with 1 mM melatonin controlled growth and impaired invasion and metastasis by disrupting cytoskeleton formation [ 486 ] while high-dose melatonin (5 mg/m 2 /day to 700 mg/m 2 /day) showed stable, favorable responses in human subjects diagnosed with advanced malignant melanoma [ 487 ]. Melatonin also prevented the aggressive phenotype shifts in breast cancer cell lines maintained under acidosis conditions by modulating proliferation and apoptosis [ 488 ].…”

Tunneling nanotubes and mesenchymal stem cells: New insights into the role of melatonin in neuronal recovery

“…The molecular mechanisms by which melatonin enhances TNT formation and functionality remain unknown and deserve intensive study. A modulatory effect of melatonin on the cytoskeleton has been reported in different types of cells [102][103][104] and cytoskeletal rearrangements seem to protect the neuro-cytoskeleton from damage caused by free radicals, which, in turn, contributes to cell survival.…”