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

Abstract

Abstract Melatonin suppresses tumor development. However, the exact relationship between melatonin and cancer stem cells ( CSC s) is poorly understood. This study found that melatonin inhibits colon CSC s by regulating the Pr P C ‐Oct4 axis. In specimens from patients with colorectal cancer, the expressions of cellular prion protein (Pr P C ) 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 ALDH 1A1 by downregulating Pr P C . In this way, tumor growth, proliferation, and tumor‐mediated angiogenesis were suppressed. In colorectal CSC s, PRNP overexpression protects Oct4 against inhibition by 5‐ FU and melatonin. In contrast, Nanog, Sox2, and ALDH 1A1 have no such protection. These results indicate that Pr P C directly regulates Oct4, whereas it indirectly regulates Nanog, Sox2, and ALDH 1A1. Taken together, our findings suggest that co‐treatment with anticancer drug and melatonin is a potential therapy for colorectal cancer. Furthermore, Pr P C maintains cancer stemness during tumor progression. Therefore, targeting the Pr P C ‐Oct4 axis may prove instrumental in colorectal cancer therapy.