Work

Loss of Regulator of G Protein Signaling 11 Promotes Protumorigenic Features in Pancreatic Cancer

Year: 2025

Type: article

Abstract: 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. In this study, we demonstrate the regulator of G protein signaling (RGS) 11 as a key target of CNT1, with potent tumor-suppressive properties in PDAC. Compared with normal human pancreas, RGS11 expression is diminished in human PDAC tissues which correspond with the reduced patient survival times. In addition, quasimesenchymal pancreatic tumor cell lines with accelerated growth, metastatic propensity, and innate resistance to nucleoside analogs showed relatively lower RGS11 expression than their epithelial counterparts. Interestingly, RGS11 levels reversibly modulated the epithelial-mesenchymal transition 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 quasimesenchymal 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 antitumorigenic features in PDAC with therapeutic and prognostic values.

Source: Molecular Cancer Research

DOI: 10.1158/1541-7786.mcr-25-0144

Authors: Tejinder Kaur, Debasis Nayak, Arnav Joshi, Junan Li, Amy Hite, Rajgopal Govindarajan

Institutions: The Ohio State University, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Language: English

Topic: Pancreatic and Hepatic Oncology Research

Subfield: Oncology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences