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

Abstract

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.

• Authors: Jun Hee Lee, Chul Won Yun, Yong-Seok Han, SangMin Kim, Dongjun Jeong, Hyog Young Kwon, Hyeongjoo Kim, Moo-Jun Baek, Sang Hun Lee
• Journal: Journal of pineal research (J Pineal Res) Vol. 65 Issue 4 Pg. e12519 (Nov 2018) ISSN: 1600-079X [Electronic] England
• PMID: 30091203 (Publication Type: Journal Article)
• Copyright: © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Octamer Transcription Factor-3
• POU5F1 protein, human
• Prion Proteins
• Prions
• RNA, Small Interfering
• SOX2 protein, human
• SOXB1 Transcription Factors
• Aldehyde Dehydrogenase 1 Family
• Aldehyde Dehydrogenase
• ALDH1A1 protein, human
• Retinal Dehydrogenase
• Melatonin
• Fluorouracil

Topics

• Aged
• Aldehyde Dehydrogenase (metabolism)
• Aldehyde Dehydrogenase 1 Family
• Autophagy (drug effects, genetics)
• Colon (drug effects, metabolism)
• Colonic Neoplasms (metabolism)
• Female
• Flow Cytometry
• Fluorouracil (pharmacology)
• Humans
• Immunohistochemistry
• Male
• Melatonin (pharmacology)
• Middle Aged
• Neoplastic Stem Cells (drug effects, metabolism)
• Octamer Transcription Factor-3 (metabolism)
• Prion Proteins (metabolism)
• Prions (metabolism)
• RNA, Small Interfering (genetics)
• Retinal Dehydrogenase
• SOXB1 Transcription Factors (metabolism)