The mechanisms and roles of melatonin in gastrointestinal cancer

Abstract

Gastrointestinal (GI) cancer is a global health problem with wide lesions and numerous cases. The increased morbidity and mortality of GI cancer is a socio-economic challenge for decades to come. Melatonin, a nature indolamine, exerts a crucial role in molecular interactions involved in multiple functional and physiological processes. Increasing evidence indicates that melatonin can modulate GI tract, decrease the occurrence of GI cancer, and enhance the sensitivity to chemoradiotherapy. However, little is known about the exact role of melatonin in anti-carcinogenesis. In this review, we discuss the action of the beneficial effects of melatonin in GI carcinogenesis. Furthermore, we compile the understanding of the role of melatonin in GI cancer, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), and pancreatic cancer (PC). In addition, the potential therapeutic application and clinical evaluation of melatonin in GI cancer are also discussed.

Keywords: carcinogenesis; cellular lifecycle; gastrointestinal cancer; immunity; melatonin.

Figure 1

The formation of melatonin in the organism. First, L-tryptophan (L-Trp) is hydroxylated to 5-hydroxytryptophan (5-hydroxy Trp). 5-hydroxy Trp is then decarboxylated to 5-hydroxytryptamine (5-HT), which is then acetylated to N-acetyl-5-hydroxytryptamine (N-acetyl 5-HT). Finally, N-acetyl 5-HT is methylated to N-acetyl-5-methoxytryptamine, also known as melatonin.

Figure 2

The effects of melatonin on various gastrointestinal cancer. This figure shows the examples of several common gastrointestinal cancer (including EC, GC, HCC, PC, and CRC) where melatonin exhibits protective effects EC, esophageal cancer; GC, gastric cancer; HCC, hepatocellular carcinoma; PC, pancreatic cancer; CRC, colorectal cancer.

Figure 3

Mechanisms of melatonin in GI carcinogenesis. Melatonin plays a role in anti-carcinogenesis mainly through the following ways, including modulating cellular lifecycle, regulating immunity function, and involving several oncogenic signaling pathways. Melatonin can induce cell apoptosis via regulating multiple genes (cyt c, Bcl-2, Fas) and inhibit proliferation by arresting cancer cell cycle (cyclin D1, cyclin B1, CDK1, CDK 4). Moreover, it can also influence the angiogenesis and metastasis by modulating HIF-1, VEGF, MMP, etc. Secondly, melatonin is a regulator of immunity. It mediate the immune function mainly through increasing the counts of immune cells, enhancing the expansion of splenic zones, and activating the function of T/B cells. Thirdly, melatonin can inhibit carcinogenesis through specific signaling pathways, such as p38/MAPK, NF-κB, PI3K/Akt, and Wnt/β-catenin. Bcl-2, B-cell lymphoma-2; cyt c, cytochrome c; EMT, epithelial-mesenchymal transition; FasL, Fas ligand; HIF-1, hypoxia-inducible factor 1; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinases; NF-κB, nuclear factor-kappa B; PI3K, phosphoinositide 3 Kinase; VEGF, vascular endothelial growth factor.