Cell proliferation, differentiation, senescence and apoptosis are structural and functional bases of organism growth, development, aging and death, respectively (18). Cells deviate from the normal lifecycle due to internal or external factors, which may lead to the occurrence of cancer. It has been reported that melatonin act as a loyal defender against GI cancer through regulating cellular apoptosis, proliferation, metastasis, and angiogenesis. With the relevant cumulative findings, herein we investigate the action and role of melatonin in GI carcinogenesis.

Apoptosis, also known as programmed cell death (PCD), is a physiologic cell death that is distinct from necrosis. It is an active “suicide” extinction process after cells are stimulated by certain signals. Recent in-depth studies on biological cell death pathways have shown that the attenuation of apoptosis is closely related to the formation of GI cancer (19). There is increasing evidence that melatonin promotes PCD in GI cancer (20). Cytochrome c (cyt c) is release into the cytoplasm when the cells are stimulated, and triggers an enzymatic cascade that leads to apoptosis (21). The B-cell lymphoma-2 (Bcl-2) family mediates the intrinsic apoptosis pathway with both anti-apoptotic and pro-apoptotic effects (22). Fas, a transmembrane protein, binds to Fas ligand (FasL) to initiate the transduction of apoptotic signals and induce apoptosis (23). Mechanistically, melatonin can modulate the expression of multiple genes associated with apoptosis, such as cytosolic cyt c, Bcl-2, Fas, etc (20, 24).

Rampant proliferation is another important characteristics of all cancers. The carcinogenesis is the result of the imbalance between cell proliferation and apoptosis. It has been reported that melatonin exerts an obvious anti-proliferation effect via arresting cancer cell cycle (25). For example, Liu et al. proved that melatonin attenuated the expression of cyclin D1 and CDK4 in G1 phase, and cyclin B1 and CDK1 in G2/M phase of human osteosarcoma cells (26). Moreover, the anti-proliferative efficacy of melatonin have been demonstrated in GC and HCC cell lines (27).

Additionally, increasing evidence indicates that melatonin is also involved in angiogenesis and metastasis in GI cancer. Cancer angiogenesis is known to be an important feature of metastasis responsible for cancer death. Melatonin has the capacity to reduce the migration and neovascularization of cancer cells. For instance, Wang et al. showed that melatonin suppressed IL-1β-induced lung metastasis of GC by downregulating the expression of matrix metalloproteinases (MMP), and nuclear factor-kappa B (NF-κB) p65 (28). Moreover, melatonin can also inhibits cancer angiogenesis via attenuating hypoxia-inducible factor (HIF)-1 and decreasing vascular endothelial growth factor (VEGF) expression (29).

Interactions between immune cells and cancer cells exert a crucial role in cancer development (30). Since MT are widely present in immune system, melatonin is involved in regulating immune function. Studies have shown that melatonin increases the cells of the innate immunity, such as neutrophil, macrophages, and lymphocytes counts (31). Luo et al. demonstrated that melatonin modulated the activation of T/B cells, thus playing a key role in stabilizing immune balance (32). Besides, Liu et al. indicated that melatonin inhibited GC cell growth by down-regulating the expressions of CD4 (+) and CD25 (+) regulatory T cells (Tregs) and Forkhead box p3 (Foxp3) in GC (33). Moreover, melatonin is also proved to enhance the expansion of splenic zones (34). In addition, it has been shown that melatonin participates in the regulation of cytokine production (35).

Signaling pathways are intertwined into networks in physiological processes of systemic organs throughout the body and play important roles in human health and disease. The disruption of multiple signaling pathways is closely involved in the progression of diverse cancers. It has been indicated that melatonin could regulate the mediators in oncogenic signaling pathways, such as NF-κB, phosphoinositide 3 Kinase (PI3K)/Akt, p38/mitogen-activated protein kinase (MAPK), and Wnt/β-catenin axis (36–38). For example, Liu et al. reported that melatonin decreased Rho−associated protein kinase (ROCK) expression via p38/MAPK signaling pathway, thus inhibiting the migration of CRC cells (39). The transdifferentiation of epithelial cells into motile mesenchymal cells, known as epithelial-mesenchymal transition (EMT), is a process that enhances the invasiveness and anti-apoptotic capabilities of cancer cells (40). Wang et al. proved that melatonin suppressed EMT in GC via attenuation of IL−1β/NF−κB/MMP2/MMP9 axis (41).

Esophageal cancer (EC) refers to malignant tumors of esophageal epithelial origin, which is mainly manifested as choking sensation when swallowing food, foreign body sensation, retrosternal pain, or obvious dysphagia (67). It is one of the most common gastrointestinal cancer with regional variations in morbidity and mortality. The two major subtypes of EC are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Studies have shown that smoking, alcohol consumption, obesity, aging, male sex, Barrett’s esophagus, and gastroesophageal reflux disease (GERD) consist of the potential risk factors for EC (68, 69).

Melatonin has been shown to afford esophago-protection via diverse mechanisms. Firstly, it enhances tumor cell sensitivity to chemotherapy drugs. In 2016, Lu et al. demonstrated that melatonin improved ESCC cell sensitivity to 5-fluorouracil (5-FU) via suppressing the Erk and Akt pathway (43). Furthermore, Zhang et al. proved that melatonin significantly enhanced 5-FU-mediated suppression of esophageal cancer cell proliferation and migration by regulating enhancer of zeste homolog 2 (EZH2) (45). Histone methyltransferase EZH2, a catalytic component of polycomb repressive complex 2 (PRC2), is highly expressed in the development of esophageal cancer (70). Secondly, melatonin exerts anti-inflammatory and anti-oxidant effects in EC. NF-κB induces the expression of multiple genes through the activation of stimulating factors and produces multiple cytokines involved in inflammatory responses. Gu et al. revealed that melatonin inhibited cell invasion via down-regulating the NF-κB signaling pathway in EC (46). Thirdly, melatonin is involved in the regulation of cell cycle. It has been reported that melatonin causes cell cycle arrest and affects the percentage of abnormalities in different phase (47).

Gastric cancer (GC) is a predominant malignancy with the second leading cause of cancer death worldwide (71). The lifestyle, genetics, helicobacter pylori (H. pylori) infection, and epigenetics are potential risk factors for GC (72). H. pylori is a major cause of gastric carcinogenesis by enhancing the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and inducing local ulceration and inflammation (73). According to the pathological types, GC can be divided into adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, medullary carcinoma and undifferentiated cell carcinoma, among which adenocarcinoma is the most common. Gastroscopy is the preferred method for GC, and gastric biopsy is the “gold standard” for the diagnosis of GC.

Growing evidence demonstrates that melatonin exerts gastroprotective effects in GC through multiple mechanisms, including increasing blood flow, reducing inflammation, scavenging free radicals, and inhibiting MMP (41, 74, 75). On the one hand, melatonin has been shown to play a role in affecting the growth of GC itself. Liu et al. revealed that melatonin inhibited GC cell progression via the NF-kB signaling pathway (48). They proved that melatonin suppressed cell growth by directly reducing ROS production, while indirectly decreasing the level of MMP2 and MMP9 in cancer-associated fibroblasts (CAFs) in gastric cancer cells. Moreover, melatonin was reported to inhibit the proliferation of GC cells via modulating miR-15-5p-small mothers against decapentaplegic homolog 3 (Smad3) pathway (49). Additionally, it has been demonstrated that melatonin induces GC cell apoptosis via regulating diverse signaling pathways (76, 77). For example, Li et al. noted that melatonin stimulated GC cell apoptosis by mediating NF-kB and MAPK signaling pathways (50). Apart from mentioned above, the effects of melatonin on angiogenesis and differentiation are also involved in the progression of GC (51). On the other hand, melatonin has also been proven to be effective in reducing metastasis exacerbations. There is increasing evidence that GC migration is significantly reduced following melatonin treatment. In a study, decreased lung metastasis in GC after melatonin treatment was associated with the downregulation of MMP2, MMP9, and NF-kB p65 (28). Wu et al. indicated that melatonin blocked EMT and peritoneal dissemination through NF-κB cleavage and calpin-mediated C/EBPβ (52). Besides, melatonin was reported to inhibit the migration of GC via remodeling tight junction (78).

Hepatocellular carcinoma (HCC) is a major global health challenge and the fourth leading cause of cancer-related death worldwide. HCC is prevalent to spread in the liver through the portal vein system, forming intrahepatic metastasis, and also easy to form tumor thrombus in the portal vein, causing the manifestation of portal hypertension (79). A commonly used tumor marker for HCC is alpha-fetoprotein (AFP), especially when it is significantly elevated, high vigilance should be exercised. For people with hepatitis infection, liver cirrhosis and family history of liver cancer, regular screening for HCC should be carried out for early detection, diagnosis and treatment (80).

Emerging evidence demonstrates that melatonin exerts anti-cancer activity on HCC. It is worth noting that melatonin reverses apoptosis resistance and activates both intrinsic and extrinsic pathways of apoptosis in HCC (54). Zha et al. found that melatonin stimulates endoplasmic reticulum (ER) stress-induced apoptosis in HCC (53). Moreover, melatonin is involved in the regulation of HCC by modulating a variety of transcription factors and related pathways to inhibit cell proliferation and invasiveness (54). In addition, melatonin has been proven to restrain HCC progression via regulating non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) (55, 56). Besides, melatonin could sensitize HCC cell to chemotherapy (57). Recent studies have shown that melatonin suppresses glycolysis in HCC cells by down-regulating mitochondrial respiration and mammalian target of rapamycin complex 1 (mTORC1) activity (58).

Colorectal cancer (CRC) is considered as the second most common cancer worldwide and the incidence of CRC increases with age (81). Adenocarcinoma is the most common pathological type of CRC. In recent years, the morbidity and mortality of colorectal cancer have shown an increasing trend, which should be paid more attention to. Chemoradiotherapy is the last-line treatment for advanced CRC with significant side effects. Therefore, it is urgent to explore an anti-cancer agent in CRC.

Melatonin holds promise as an adjunctive treatment for advanced CRC. The entero-endocrine (EE) cells in GI tract mucosa are the main source of intestinal melatonin (82). Increasing evidence evaluates the effects and safety of melatonin. It has been reported that melatonin is associated with various health outcomes in heterogeneous populations (83). Mechanically, it has been reported that melatonin prevent and delay the progression of CRC by suppressing the proliferation and inducing apoptosis of CRC cells. Ji et al. demonstrated that melatonin regulated the miR-34a/449a cluster, thus influencing the cell cycle in CRC (59). Yun et al. noted that melatonin promoted CRC cell apoptosis via superoxide-mediated ER stress (60). Besides, melatonin promotes chemotherapeutic drug-mediated apoptosis of CRC cells by enhancing oxidative stress (61). In addition to its role in sensitivity to chemotherapeutic agents, melatonin also sensitizes human CRC cells to γ-ray ionizing radiation both in vitro and in vivo (62). Interestingly, studies have pointed out that melatonin plays a preventive and therapeutic role in CRC by regulating lipid metabolism and gut microbiota (63). Menadione, a synthetic form of vitamin K, is known to stimulate an increase in intracellular ROS and alter the oxidative status of cancer cells (84). Collin et al. confirmed that menadione plus melatonin on Caco-2 cells could reduce cell proliferation, induce reactive nitrogen species formation, enhance superoxide anion content, and increase catalase activity, suggesting the potential as adjuvant therapy for CRC acting on different oncogenic pathways (85). Kvietkauskas et al. designed a study to explore the combined role of melatonin and glycine in CRC liver metastasis (86). They found that supplementation with melatonin and glycine reduce CRC liver metastasis growth by acting as natural antiangiogenic molecules.

Pancreatic cancer (PC) is the source of an increasing number of cancer-related deaths with a low survival rate. The high mortality rate of PC is likely to be associated with the absence of early symptoms and therefore delayed diagnosis, as well as high resistance to chemoradiotherapy. PC is classified as resectable, borderline, locally advanced and metastatic with greatly varied treatment among them (87). The sensitivity of computed tomography (CT) and magnetic resonance imaging (MRI) in detecting PC was as high as 96% and 93.5%, respectively (88). Despite significant advances in the treatment of PC, including improved surgical techniques and refined adjuvant and neoadjuvant therapies, the incidence and mortality of PC have not decreased significantly worldwide. We therefore emphasize the historical perspective of PC treatment, highlight the prevention strategies, and identify more integrated approaches.

Growing evidence supports the therapeutic benefits of melatonin in the management of PC. Studies have shown that a variety of inflammatory pathways are closely related to the pathological process of PC (89). Melatonin stimulates cancer cell apoptosis by acting as an inflammatory inhibitor, an oxidative stress modulator, a VEGF inhibitor, a heat shock proteins (HSPs) inhibitor, etc. (64, 65). Firstly, it protects pancreatic tissue from inflammatory damage and oxidative stress via activating anti-oxidant enzymes and scavenging ROS and RNS. Secondly, melatonin decreases endothelial cells proliferation and reduces angiogenesis by inhibiting VEGF. Thirdly, high concentration of melatonin regulate Bax/Bcl protein balance, thus stimulating the expression of caspase-3 and caspase-9, while low level of melatonin produce anti-apoptotic HSPs, such as HSP27 and HSP90, thereby preventing the activation of caspase-3. Moreover, it has been found that melatonin is involved in enhancing the efficacy of chemotherapy and decreasing side effects. Fang et al. found that melatonin and sorafenib synergistically inhibited PC through MR and PDGFR-β/STAT3 signal pathway (66). Melatonin was also proved to enhance the chemosensitivity to gemcitabine in PC (90). The metabolites of L-Trp and melatonin are called kynuramines, of which N1-acetyl-5-methoxy-kynuramine (AMK) and N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK) are the best known melatonin derivatives (91). It has been shown that melatonin precursor L-Trp and the melatonin derivatives kynuramines, may be related to the physiological and functional failure of the pancreas, leading to the impairment of pancreatic function and anti-cancer ability (92).