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J Pineal Res. 2018 Nov;65(4):e12519. doi: 10.1111/jpi.12519. Epub 2018 Aug 24.

Melatonin and 5-fluorouracil co-suppress colon cancer stem cells by regulating cellular prion protein-Oct4 axis.

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Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul, Korea.
Department of Pathology, College of Medicine, Soonchunhyang University, Cheonan, Korea.
Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan, Korea.
Soonchunhyang Medical Science Research Institute, College of Medicine, Soonchunhyang University, Cheonan, Korea.
Department of Surgery, College of Medicine, Soonchunhyang University, Cheonan, Korea.
Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan, Korea.


Melatonin suppresses tumor development. However, the exact relationship between melatonin and cancer stem cells (CSCs) is poorly understood. This study found that melatonin inhibits colon CSCs by regulating the PrPC -Oct4 axis. In specimens from patients with colorectal cancer, the expressions of cellular prion protein (PrPC ) and Oct4 were significantly correlated with metastasis and tumor stages. Co-treatment with 5-fluorouracil (5-FU) and melatonin inhibited the stem cell markers Oct4, Nanog, Sox2, and ALDH1A1 by downregulating PrPC . In this way, tumor growth, proliferation, and tumor-mediated angiogenesis were suppressed. In colorectal CSCs, PRNP overexpression protects Oct4 against inhibition by 5-FU and melatonin. In contrast, Nanog, Sox2, and ALDH1A1 have no such protection. These results indicate that PrPC directly regulates Oct4, whereas it indirectly regulates Nanog, Sox2, and ALDH1A1. Taken together, our findings suggest that co-treatment with anticancer drug and melatonin is a potential therapy for colorectal cancer. Furthermore, PrPC maintains cancer stemness during tumor progression. Therefore, targeting the PrPC -Oct4 axis may prove instrumental in colorectal cancer therapy.


Oct4; cancer stem cell; cellular prion protein; melatonin

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