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

Wen Jui Lee, Li Ching Chen, Juo Han Lin, Tzu Chun Cheng, Ching Chuan Kuo, Chih Hsiung Wu, Hui Wen Chang, Shih Hsin Tu, Yuan Soon Ho

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)4821-4835
Number of pages15
JournalCancer Medicine
Issue number10
Publication statusPublished - Jan 1 2019


  • autophagy
  • hyaluronan synthase 3
  • melatonin
  • N2a cell differentiation
  • neuroblastoma

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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