Dictyostelium differentiation‐inducing factor‐1 induces glucose transporter 1 translocation and promotes glucose uptake in mammalian cells

The differentiation‐inducing factor‐1 (DIF‐1) is a signal molecule that induces stalk cell formation in the cellular slime mold Dictyostelium discoideum, while DIF‐1 and its analogs have been shown to possess antiproliferative activity in vitro in mammalian tumor cells. In the present study, we investigated the effects of DIF‐1 and its analogs on normal (nontransformed) mammalian cells. Without affecting the cell morphology and cell number, DIF‐1 at micromolar levels dose‐dependently promoted the glucose uptake in confluent 3T3‐L1 fibroblasts, which was not inhibited with wortmannin or LY294002 (inhibitors for phosphatidylinositol 3‐kinase). DIF‐1 affected neither the expression level of glucose transporter 1 nor the activities of four key enzymes involved in glucose metabolism, such as hexokinase, fluctose 6‐phosphate kinase, pyruvate kinase, and glucose 6‐phosphate dehydrogenase. Most importantly, stimulation with DIF‐1 was found to induce the translocation of glucose transporter 1 from intracellular vesicles to the plasma membranes in the cells. In differentiated 3T3‐L1 adipocytes, DIF‐1 induced the translocation of glucose trasporter 1 (but not of glucose transporter 4) and promoted glucose uptake, which was not inhibited with wortmannin. These results indicate that DIF‐1 induces glucose transporter 1 translocation and thereby promotes glucose uptake, at least in part, via a inhibitors for phosphatidylinositol 3‐kinase/Akt‐independent pathway in mammalian cells. Furthermore, analogs of DIF‐1 that possess stronger antitumor activity than DIF‐1 were less effective in promoting glucose consumption, suggesting that the mechanism of the action of DIF‐1 for stimulating glucose uptake should be different from that for suppressing tumor cell growth.