Synthetic oleanane triterpenoid derivative CDDO-Me disrupts cellular bioenergetics to suppress pancreatic ductal adenocarcinoma via targeting SLC1A5.

Abstract

To investigate the potential antitumor activity of synthetic triterpenoid, methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate(CDDO-Me) in pancreatic ductal adenocarcinoma (PDAC), MTT cytotoxicity assay, and xenograft nude mice assay were performed to evaluate tumor growth in vitro and in vivo. Seahorse XFe96 bioenergetics analyzer was applied to determine aerobic glycolysis and mitochondrial respiration. Western blot and quantitative reverse transcription-polymerase chain reactions areused to detect protein and messenger RNA transcripts of SLC1A5 and metabolic enzymes. We confirmed the strong antitumor activity of CDDO-Me in suppressing PDAC growth. Mechanistically, we demonstrated CDDO-Me induced mitochondrial respiration and aerobic glycolysis dysfunction. We also verified CDDO-Me downregulated glutamine transporter SLC1A5, resulting in excessive reactive oxygen species(ROS) levels that suppressed tumor growth. Moreover, we confirmed thatSLC1A5 depletion reduced the ratio of glutathione/oxidized glutathione.We also found CDDO-Me could inhibit N-linked glycosylation of SLC1A5, which promotes protease-mediated degradation. Finally, we confirmed SLC1A5 was significantly overexpressed in PDAC and closely correlated with the poor prognosis of PDAC patients. Our work uncovers CDDO-Me is effective at suppressing PDAC cell growth in vitro and in vivo and illuminates CDDO-Me caused excessive ROS and cellular bioenergetics disruption which contributed to CDDO-Me inhibited PDAC growth. Our data highlights CDDO-Me could be considered a potential compound for PDAC therapy, and SLC1A5 could be a novel biomarker for PDAC patients.