Abstract
Pancreatic cancer (PDAC) cells experience nutrient starvation in a poorly perfused tumor microenvironment. Metabolic dependencies that protect PDAC cells from detrimental oxidative stress in a nutrient-restricted niche represent as tumor-specific targets. While the role of mitochondria in supporting energy production and biosynthetic requirements of cells has been well investigated, their contribution to maintaining intracellular redox homeostasis when PDAC cells are exposed to nutrient deprivation is unknown. Our results demonstrate that cytosolic transport of citrate via SLC25A1 confers a survival advantage to PDAC cells by protecting them from ferroptosis, a well-established iron-dependent cell death mechanism, under nutrient-limited conditions. Employing selective SLC25A1 inhibitor or targeting mitochondrial OXPHOS dramatically reduced GPX4 expression and PDAC cell viability. Rescuing GPX4 expression with the products of both ACLY and ACO1-dependent pathways uncovered their critical role in conferring survival advantage under metabolic stress. Importantly, exogenous expression of GPX4 reversed redox imbalance and metabolic discordance resulting from the lack of SLC25A1 activity, indicating the requirement of citrate-induced GPX4 expression to support mitochondrial health and function. As observed with cultured cells under nutrient limitation, SLC25A1 function was revealed to be indispensable in pancreatic tumor microenvironment, and the reduced growth, due to the lack of SLC25A1 activity, was rescued with antioxidant NAC in preclinical models of PDAC. Lastly, SLC25A1 suppression was accompanied by elevated glutamine metabolism, and combination therapy with pharmacologic inhibitors of SLC25A1 and glutaminase inhibitor CB-839 dramatically suppressed tumor growth, highlighting this combinatorial approach as a potential therapeutic strategy in PDAC.
Competing Interest Statement
J.M.S. is a coauthor on patents on IDH1 inhibitors, and has received sponsored research funding from the Barer Institute and has patents pending to Wistar Institute. He also owns equity or consults with Alliance Discovery, Syndeavor Therapeutics, Barer Institute, and Context Therapeutics. A.V.-G. and Loyola University Chicago filed U.S. Provisional Patent Application No. 63/672,600 on July 17, 2024 directed to Compositions and Methods for Treating Pancreatic Cancer.
Footnotes
The details about our submission, including doi information, overlap with our figure panels in the figures (main and supplementary figures), so the audience can not see the figures' contents well.
