Mechanistic studies on the inhibitory effects of selenite on tumor invasion and apoptosis

Abstract

Selenium, an essential biological trace element, has been shown to reduce and prevent the incidence of cancer. Our previous studies have shown that selenite is involved in the chemoprevention of cancer and induction of apoptosis of cancer cells. In this study, we demonstrate that selenite also inhibits the invasion of tumor cells. Cancer cell invasion requires coordinated processes, such as changes in cell-cell and cell-matrix adhesion, degradation of the extracellular matrix, and cell migration. We found that selenite inhibited invasion of HT1080 human fibrosarcoma cells. Adhesion of HT1080 cells to the collagen matrix was also inhibited by treatment with selenite, but cell-cell interaction and cell motility were not affected with selenite. Moreover, selenite reduced expression of matrix metalloproteinase-2,-9 and urokinase type plasminogen activator, which are involved in matrix degradation, but increased a tissue inhibitor of metalloproteinase-1. This inhibitory effect of selenite on the proteases expressions was mediated by the suppression of transcription factors, NF-_κB and AP-1. However, selenate showed no remarkable effects on above all the steps of cancer cell invasion. The relationship between selenium and signal molecules has not been well elucidated. It was found that physiological concentration of selenite, less than 3 μM, reduced ASK1 activity and induced of PI3-Kinase/Akt pathways in HT1080 cells. Duration of these signal molecules by selenite was much longer than that by growth factors and other stresses. The longer duration time of these signal molecules may be important to maintain normal functions against stresses. Selenite increased cell proliferation through upregulation of Bcl-2 expression, mitochondrial membrane potential, ATP generation and glucose uptake mediated by PI3-Kinase pathway. High concentration of $H_2O_2$ increased an apoptotic signal molecule, ASK1, which resulted in Bcl-2 downregulation, membrane potential disruption, decr...