Loss of Regulator of G protein signaling 11 promotes pro-tumorigenic features in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, associated with early metastasis, drug resistance and poor outcomes. We previously demonstrated a putative tumor suppressive role for concentrative nucleoside transporter 1 (CNT1) in PDAC. Here we demonstrate the regulator of G protein signaling (RGS) 11 as a key target of CNT1, with potent tumor suppressive properties in PDAC. Compared to normal human pancreas, RGS11 expression is diminished in human PDAC tissues which correspond with the reduced patient survival times. In addition, quasi-mesenchymal pancreatic tumor cell lines with accelerated growth, metastatic propensity, and innate resistance to nucleoside analogs showed relatively lower RGS11 expression than the epithelial counterparts. Interestingly, RGS11 levels reversibly modulated the epithelial-mesenchymal transition (EMT) of human PDAC cell lines influencing the chemotherapeutic sensitivities of anti-PDAC drugs. Additionally, stable lentiviral-mediated RGS11 expression reduced the cellular proliferation and colony establishment, increased the apoptotic index, and decreased the migratory and invasive abilities in quasi-mesenchymal tumor cell lines, whereas RGS11 depletion in epithelial tumor cell lines showed opposite effects. Global transcriptomic analysis revealed RGS11 replenishment in PDAC cells to suppress CD44-directed stemness features with significant reprogramming of the PDAC oncogenic landscape. Furthermore, RGS11 reduced the primary tumor burden and metastatic occurrence in a mouse model of PDAC. Together, these findings uncover RGS11 as a key target of CNT1 that exhibits therapeutic potential for intervention of aggressive PDAC. Implications: RGS11 identified as a downstream target of a gemcitabine transporter CNT1 exerts potent anti-tumorigenic features in pancreatic ductal adenocarcinoma with therapeutic and prognostic values.