Two broad areas of research are suggestive of a role for melatonin in the incidence and progression of cancer. The first includes the many studies of melatonin as an oncostatic agent at the cellular level, one that can slow the progression of cancer. The majority of these studies have focused on breast or prostate cancer and implicate melatonin in one or more of the following processes: decreased cell proliferation; decreased metastasis; increased apoptosis; and increased differentiation. Although MT1 receptors have been identified and activation of signaling pathways (see Figure 1) confirmed in many cancer cell types, the mechanisms by which melatonin exerts these effects have not been elucidated.
Fig1. Membrane signaling by the melatonin receptor. The MT1 and MT2 receptors for melatonin, both G-protein coupled receptors, use one of two signaling pathways, depending on the cell type. On the left is shown the interaction of Gi with adenyl cyclase to decrease cyclic AMP levels and therefore cyclic AMP-dependent protein kinase activity (PKA). On the right is shown the interaction of Gq with phospholipase C (PLC) leading to the cleavage of phosphatidyl inositol diphosphate (PIP2) into inositol triphosphate (IP3) and diacylglycerol (DAG). These second messengers stimulate increased intracellular Ca2+ and protein kinase C (PKC), respectively. The downstream effects of these events at the membrane vary with cell type.
The other major type of evidence implicating melatonin in the onset and/or progression of cancer, again particularly that of the breast and prostate, are observations of the association between exposure to disruption in the normal dark/light rhythms, and therefore of melatonin production, on cancer incidence in humans and progression in experimental animals. As one example of the former, many studies have been carried out in people who engage in night shift work, such as those in the health care, transportation, communication, and hospitality sectors. In general an inverse relationship between melatonin production, altered by changes in work schedules, and cancer incidence has been observed. In an experimental setting with animal models, constant light exposure, dim light during dark ness, or pinealectomy all stimulate cancer initiation or growth. Taken together, these results provide support for a role for melatonin in cancer incidence and possibly progression in humans, but a firm cause-and-effect relationship remains to be established.
