Melatonin selectively influences the transcription of pluripotency and differentiation markers in human non-cancer cells

Abstract

Melatonin (MEL) may influence the efficiency of reprogramming both by somatic cell nuclear transfer and by direct induction of pluripotent stem cells (iPSC) through a yet unidentified mechanism. Transcription factors linked to cell reprogramming and cell signalling may be differentially expressed according to cell differentiation status. To address the effect of MEL on the expression of transcription factors linked to reprogramming, we used two distinct in vitro models of cellular plasticity: human foreskin fibroblasts (HFF) and primary human granulosa-lutein cells (GLC). Realtime quantitative polymerase chain reaction (qRT-PCR) analysis revealed amplification of transcripts for KLF4, MYC and NANOG in both cell types. In GLC, treatment with 10 nmol/L of MEL provoked significant up-regulation of the expression of MYC and NANOG compared to controls. KLF4 expression was not altered in GLC but was significantly down-regulated in MEL-treated HFF cells. Alterations in the expression of ERK1/2 and pERK1/2 in GLC as analyzed by Western blot were not observed regardless of the MEL treatment. On the contrary, HFF cells responded to MEL treatment with 1.6-fold higher levels of pERK1/2 compared to the non-treated controls. Our data suggest that the activation of MT1 melatonin receptor is probably related to phosphorylation of ERK1/2 at least in expanding HFF, which subsequently may act to alter gene expression and regulate cell fate. In conclusion, we demonstrated for the first time, the selective effect of MEL in vitro at physiological concentration on transcription factors regulating pluripotency and differentiation in human non-cancer cells according to cell differentiation status.

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

“…In non-cancerous settings, melatonin has been demonstrated to enhance pluripotency and stem cell proliferation at 500 ng/L (2.15 nmol/L) by inducing the expression of stem cell markers including Oct4 [ 822 ]. At 10 nmol/L concentration in human non-cancer cells, melatonin selectively upregulated transcription of pluripotency and differentiation markers such as NANOG [ 823 ], completely contrary to findings in ovarian cancer stem cell experiments where melatonin inhibited the invasion and migration of cancer stem cells by inhibiting NANOG expression, albeit at exceptionally high concentrations between 3.4 and 6.3 mM [ 824 ]. It is tempting to hypothesize that at higher concentrations, melatonin can modulate inhospitable environment to attenuate PrP C stress responses, whereas lower levels stimulate and support the natural, physiological protective activities of prions.…”

Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease

“…Recent research from our laboratory demonstrated that melatonin treatment stimulates the expression of pERK1/2 in human foreskin fibroblasts [ 70 ]. The data suggest that the activation of MT1 melatonin receptor is probably related to phosphorylation of ERK1/2 at least in expanding fibroblasts, which subsequently may act to alter gene expression and regulate cell fate.…”