Melatonin and hyperbaric oxygen therapies suppress colorectal carcinogenesis through pleiotropic effects and multifaceted mechanisms

• Published in: International journal of biological sciences Vol. 17; no. 14; pp. 3728 - 3744
• Main Authors: Li, Yi-Chen, Chen, Chih-Hung, Chang, Chia-Lo, Chiang, John Yi-Wu, Chu, Chi-Hsiang, Chen, Hong-Hwa, Yip, Hon-Kan
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2021; Ivyspring International Publisher
• Subjects: AKT protein; Angiogenesis; Animals; Apoptosis; Cancer; Cancer therapies; Carcinogenesis; Carcinogens; Caspase-3; Cell Line, Tumor; Cell Proliferation; Cell survival; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Combined Modality Therapy; Cyclooxygenase-2; E-cadherin; Gelatinase B; Glycolysis; Humans; Hyperbaric oxygen; Hyperbaric Oxygenation; Hypoxia; Hypoxia-inducible factor 1a; In vivo methods and tests; Laboratory animals; Lung cancer; Male; Melatonin; Melatonin - therapeutic use; Mesenchyme; Metabolism; Mice; Mice, Inbred BALB C; Microenvironments; N-Cadherin; NF-κB protein; Oct-4 protein; Ovarian cancer; PD-L1 protein; Phenotypes; Poly(ADP-ribose) polymerase; Prostate cancer; Proto-Oncogene Proteins c-akt - metabolism; Research Paper; Signal Transduction; Smad3 protein; Smad3 Protein - metabolism; Software; Transforming Growth Factor beta - metabolism; Tumorigenesis; Tumors; Wound healing; Xenografts; Xenotransplantation; Taiwan; colorectal cancer; cancer stem cell; carcinogenesis; invasion; cancer growth; migration; hyperbaric oxygen; melatonin
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.62280

Colorectal cancer (CRC) is the third most common cancer worldwide. Colorectal carcinogenesis is frequently induced by hypoxia to trigger the reprogramming of cellular metabolism and gain of malignant phenotypes. Previously, hyperbaric oxygen (HBO) therapy and melatonin have been reported to alter the hypoxic microenvironment, resulting in inhibiting cancer cell survival. Accordingly, this study tested the hypothesis whether HBO and melatonin effectively inhibited CRC carcinogenesis. In vitro results indicated that melatonin therapy significantly suppressed the malignant phenotypes, including colony formation, growth, invasion, migration and cancer stemness with dose-dependent manners in CRC cell lines through multifaceted mechanisms. Similar to in vitro study, in vivo findings further demonstrated the melatonin, HBO and combined treatments effectively promoted apoptosis (cleaved-caspase 3/ cleaved-PARP) and arrested tumor proliferation, followed by inhibiting colorectal tumorigenesis in CRC xenograft tumor model. Moreover, melatonin, HBO and combined treatments modulated multifaceted mechanisms, including decreasing HIF-1α expression, alleviating AKT activation, repressing glycolytic metabolism (HK-2/PFK1/PKM2/LDH), restraining cancer stemness pathway (TGF-β/p-Smad3/Oct4/Nanog), reducing inflammation (p-NFκB/ COX-2), diminishing immune escape (PD-L1), and reversing expression of epithelial mesenchymal transition (E-cadherin/N-cadherin/MMP9). In conclusion, melatonin and HBO therapies suppressed colorectal carcinogenesis through the pleiotropic effects and multifaceted mechanisms, suggesting melatonin and HBO treatments could be novel therapeutic strategies for CRC treatment.