152-LB: Sodium-Glucose Cotransporter Inhibitor Impairs Adhesion of Cancer Cells by Increasing Shedding and Dephosphorylation of Discoid Domain Receptor

Abstract

Dapagliflozin, a selective inhibitor of the sodium/glucose cotransporter 2 (SGLT2), is used clinically to reduce circulating glucose levels in patients with type 2 diabetes mellitus by blocking the reabsorption of glucose from the kidney. Dapagliflozin is metabolized and inactivated by UDP glucuronosyltransferase 1 family, Polypeptidase A9 (UGT1A9). Dapagliflozin treatment of HCT116 cells that express SGLT2 but not UGT1A9 display loss of cell adhesion whereas HepG2 cells that express both UGT1A9 and SGLT2 are resistant to dapagliflozin. Knockdown of UGT1A9 in HepG2 cells increased dapagliflozin sensitivity whereas overexpression of UTG1A9 in HCT116 cells protect against dapagliflozin-dependent loss of cell adhesion. Dapagliflozin treatment had no effect on the cellular interaction with fibronectin, vitronectin, or laminin but induced a loss of interaction with collagen I and IV. In parallel, dapagliflozin treatment reduced the protein levels of the discoidin domain receptor 1 (DDR1) concomitant with Y792 dephosphorylation and appearance of cleaved DDR1. Concomitant with these observations, dapagliflozin increased sheddase and tyrosine phosphatase activities. Physiologically, dapagliflozin reduced tumor burden of HCT116 cells in chick chorioallantoic membrane assays. Taken together, these data present a new potential role for dapagliflozin therapy as an anti-cancer reagent in tumor cells that express SGLT2 but not UGT1A9. Disclosure J. Okada: None. S. Okada: None. M. Yamada: None.