Melatonin effects on glial tumors mitochondrial activity

Abstract

The mitochondria is a cellular organelle important not only for performing cell breathing, providing energy in the form of ATP, but also to be important for controlling the redox status and viability of the cells. In this case, the mitochondria actively participates in the intrinsic pathway of apoptosis. This organelle has its own genetic material, mitochondrial DNA (mtDNA), which has circular shape and a high number of copies. It is packaged by the protein called mitochondrial transcription factor A (TFAM) forming nucleoids complexes. Changes in the number of copies of mtDNA and TFAM expression has been associated with several pathologies, including cancer. Previous data from this laboratory have shown a significant reduction in the number of copies of mtDNA in astrocytomas of different grades of malignancy, predominantly in glioblastomas (GBMs) compared to non-malignant group. Melatonin, an amphiphilic molecule synthesized from serotonin, is the main product of the pineal gland that release it into the bloodstream during the dark phase. In addition, other sites of production of melatonin are found throughout the body and, in this case, it has autocrine or paracrine roles that is not necessarily related to timekeeping functions. Melatonin has many physiological functions such as, influencing the biological clock and regulating the secretion of various hormones and growth factors. Besides that, it is also involved in the regulation of cellular processes, including proliferation, differentiation, apoptosis, and invasion. Regarding apoptosis melatonin has a distinct action to tumor cells and non-tumor cells and therefore has been referred to as "smart killer" to protect normal cells (non-tumorigenic) and induce cell death in tumor cells, specifically activating the intrinsic apoptosis pathway. Furthermore, in normal cells melatonin has antioxidant activity because it acts as a free radical scavenger and increases the expression and activity of antioxidant enzymes. Otherwise, in tumor cells melatonin is able to increase reactive oxygen species. The use of melatonin as adjuvants in chemotherapy has shown promising results with regard to both increased efficacy of treatment and to reduction of side effects. However, the effect of melatonin on mitochondrial activity, specifically considering the content of mtDNA and the main factor required for its replication, the TFAM, has not been explored in the study of cancer. Thus, using culture linages of oligodendroglioma (HOG), less invasive astrocytomas (T98G) and glioblastoma (GBMs: U87MG and A172), we intend to evaluate the effect of melatonin on the content of the expression of mtDNA and TFAM, correlating these effects on survival, proliferation and cell migration. Furthermore, we evaluate the effect of melatonin on the intrinsic pathway of apoptosis in these cells. Our expectation is that melatonin, change the parameters via mitochondrial activation of receptor and induces cell death in cultured gliomas.