Melatonin promotes neuroblastoma cell differentiation by activating hyaluronan synthase 3-induced mitophagy

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Published on Monday, 08 July 2019

Abstract

Neuroblastoma is the second most common pediatric malignancy and has a high rate of spontaneous remission.

Uncovering the mechanisms underlying neuroblastoma cell differentiation is critical for therapeutic purposes.

A neuroblastoma cell line (N2a) treated with either serum withdrawal (<2.5%) or melatonin (>0.1 nmol/L) for 24 hours was used as a cell differentiation research model.

Interestingly, the hyaluronan synthase 3 (HAS3) protein was induced in differentiated N2a cells. N2a-allografted nude mice received an intraperitoneal injection of melatonin (40 or 80 mg/kg/day for 3 weeks).

The mean tumor volume in mice treated with 80 mg/kg melatonin was smaller than that in PBS-treated mice (1416.3 and 3041.3 mm3 , respectively, difference = 1625 mm3 , *P = 0.0003, n = 7 per group). Compared with the vector control group, N2a cells with forced HAS3 overexpression showed significantly increased neuron length (*P = 0.00082) and neurite outgrowth (*P = 0.00059). Intracellular changes in autophagy, including distorted mitochondria with abnormal circular inner membranes, were detected by transmission electron microscopy (TEM).

Our study demonstrated that HAS3-mediated signaling activated by physiological concentrations of melatonin (>0.1 nmol/L) triggered significant N2a cell differentiation.

These results provide molecular data with potential clinical relevance for therapeutic drug development.

 



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- Official Web Site: The Di Bella Method;

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- All-Trans-Retinoic Acid (ATRA - analogues and/or derivatives) - In vitro, review and in vivo publications;

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