PI5P4Kα Regulates Iron Balance to Promote Metabolic Fitness in Pancreatic Cancer
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Phosphoinositide kinases generate distinct phosphoinositides that regulate processes that maintain cellular fitness. Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) have garnered interest for their role in cancer metabolism and cellular trafficking; however, their function in pancreatic ductal adenocarcinoma (PDAC) remains unexplored. Given the unique metabolic demands of PDAC cells, which heavily rely on altered trafficking pathways to support their growth, investigating PI5P4Ks in this context may reveal critical insights. We identify PI5P4Kα as a regulator of PDAC cell fitness through its key role in maintaining iron homeostasis. PI5P4Kα depletion causes metabolic disruptions and reduced intracellular iron import, leading to the induction of apoptosis in PDAC cells that is reversed by iron supplementation. Notably, we find that PI5P4Kα knockdown suppresses tumor growth in a xenograft mouse model of PDAC. These results not only illuminate the mechanistic underpinnings of PI5P4Kα function in PDAC but also position it as a promising therapeutic target for this disease.
Graphical Abstract
Schematic representation of the novel function and implication of PI5P4Kα in PDAC . PI5P4Kα is upregulated in PDAC to support the ferro-addiction and heightened metabolic requirements of the tumor. When PI5P4Kα is inhibited, the PDAC cells undergo apoptotic cell death due to iron depletion. PI5P4Kα-depleted PDAC cells upregulate autophagy as an adaptive response but is not sufficient to defend against apoptotic cell death.
