Melatonin inhibits tumorigenicity of glioblastoma stem‐like cells via the AKT–EZH2–STAT3 signaling axis

Abstract

Glioblastoma stem-like cells (GSCs) displaying self-renewing and tumor-propagating capacity play a particularly important role in maintaining tumor growth, therapeutic resistance, and tumor recurrence. Therefore, new therapeutic strategies focusing on impairing GSC maintenance are urgently needed. Here, we used GSCs isolated from surgical specimens from patients with glioblastoma multiforme (GBM) to study the roles and underlying mechanisms associated with melatonin in GSC biology. The results showed that melatonin directly targeted glioma tumor cells by altering GSC biology and inhibiting GSC proliferation. Additionally, melatonin altered profile of transcription factors to inhibit tumor initiation and propagation. Furthermore, EZH2 S21 phosphorylation and EZH2-STAT3 interaction in GSCs were impaired following melatonin treatment. These results suggested that melatonin attenuated multiple key signals involved in GSC self-renewal and survival, and further supported melatonin as a promising GBM therapeutic.

The impact of melatonin and carbon ion irradiation on cancer stem cells

“…This analysis revealed that the downregulation of CD133 by melatonin was interrupted by blockade of the melatonin membrane receptors. The data further suggested an inhibitory effect of melatonin on GSC self-renewal and tumor-initiating capacity [17].…”

“…Chen and colleagues utilized glioblastoma stem-like cells (GSCs) isolated from surgical specimens of patients with GBM to analyze the role and underlying mechanisms associated with melatonin in GSC biology [17]. They noticed that treatment with 1 mol/L melatonin changed the shape of neurospheres.…”

“…This molecule executes its anticancer effects in various types of cancer due to its pro-apoptotic, anti-proliferative, anti-cell differentiation and anti-angiogenic actions [15,16]. Numerous studies indicate that melatonin inhibits multiple crucial signals associated with brain tumor stem cell self-renewal, viability, invasiveness, tumor growth, and therapy resistance [17][18][19]. Melatonin not only exhibits an antitumor effects on total tumor mass but also antitumor actions on subpopulations of CSCs [21].…”

EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression

“…Within hours of surgical removal, glioma specimens were enzymatically dissociated into single cells as described previously (26). For short-term in vitro expansion of GSCs, cells were cultured in Neurobasal medium (Thermo Scientific) with N2 and B27 supplements (Invitrogen), human recombinant basic fibroblast growth factor, and EGF (10 ng/mL each; Invitrogen).…”

“…Intracranial transplantation of GSCs into nude mice was performed as described previously (26). Briefly, 36 hours after lentiviral infection, live cells were counted and implanted into the right frontal lobes of athymic nude mice.…”