Inhibition of autophagy triggers melatonin-induced apoptosis in glioblastoma cells

Abstract

BackgroundAutophagy is considered to be another restorative focus for the treatment of brain tumors. Although several research have demonstrated that melatonin induces autophagy in colon cancer and hepatoma cells, there has not been any direct evidence of whether melatonin is capable of inducing autophagy in human glioma cells.ResultsIn the present research, we report that melatonin or its agonist, agomelatine, induced autophagy in A172 and U87-MG glioblastoma cells for a concentration-and time-dependent way, which was significantly attenuated by treatment with luzindole, a melatonin receptor antagonist. Furthermore, by suppressing autophagy at the late-stage with bafilomycin A1 and early stage with 3-MA, we found that the melatonin-induced autophagy was activated early, and the autophagic flux was complete. Melatonin treatment alone did not induce any apoptotic changes in the glioblastoma cells, as measured by flow cytometry. Western blot studies confirmed that melatonin alone prominently upregulated the levels of Beclin 1 and LC3 II, which was accompanied by an increase in the expression of Bcl-2, whereas it had no effect on the expression of Bax in the glioblastoma cells. Remarkably, co-treatment with 3-MA and melatonin significantly enhanced the apoptotic cell population in the glioblastoma cells, along with a prominent decrease in the expression of bcl-2 and increase in the Bax expression levels, which collectively indicated that the disruption of autophagy triggers the melatonin-induced apoptosis in glioblastoma cells.ConclusionsThese results provide information indicating that melatonin may act as a common upstream signal between autophagy and apoptosis, which may lead to the development of new therapeutic strategies for glioma.

An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress

“…This suggests that modulation of autophagy by melatonin has dual effect on cell death [ 96 ]. Similarly, disruption of autophagy sensitizes glioblastoma cells and tongue squamous cell carcinoma to melatonin-induced apoptosis [ 97 ]. Melatonin-induced autophagy is suggested to be mediated by activation of melatonin membrane receptor in tongue squamous cell carcinoma and suppression of melatonin membrane receptor-dependent autophagy may be strategy for treatment of tongue squamous cell carcinoma [ 98 ].…”

Melatonin sensitizes esophageal cancer cells to 5‑fluorouracil via promotion of apoptosis by regulating EZH2 expression

“…In recent years, studies have revealed that MLT has a number of physiological functions, such as promoting sleep, regulating jet lag, anti-aging effects, regulating immunity and antitumor effects ( 10 – 13 ). Further biological function studies have revealed that MLT can regulate the proliferation, cycle and apoptosis of cancer cells ( 14 – 16 ). MLT increases the efficacy of chemotherapeutic drugs by increasing its sensitivity of chemotherapy drugs, reducing the probability of drug resistance, and reducing the toxicity to normal cells ( 17 – 20 ).…”

Oxidative Stress—Part of the Solution or Part of the Problem in the Hypoxic Environment of a Brain Tumor

“…Moreover, it was shown that tumor cells, resistant to apoptosis, undergo necrosis when exposed to excessive metabolic stress [76,77], and that an increase in autophagy suppresses the necrosis [40,41]. Different approaches to augment intrinsic or induced apoptosis has been proposed to apply as a possible therapy against GBM [78,79]. Although apoptosis can be a measure of cell death, it is disputable whether it has a prognostic value for patient outcome in GBM [80,81].…”