Inhibition of the Na+/K+-ATPase by cardiac glycosides suppresses expression of the IDO1 immune checkpoint in cancer cells by reducing STAT1 activation
Mia Shandell, Alina L. Capatina, Samantha M. Lawrence, William J. Brackenbury, Dimitris Lagos
Abstract
levels to a lesser extent than cardiac glycoside treatment and did not affect IDO1 expression. However, ATP1A1 knockdown significantly enhanced the effect of cardiac glycosides on IDO1 expression and kynurenine production. Mechanistically, we show that cardiac glycoside treatment resulted in curtailing the length of phosphorylation-mediated stabilization of STAT1, a transcriptional regulator of IDO1 expression, an effect enhanced by ATP1A1 knockdown. Our findings reveal cross talk between ionic modulation via cardiac glycosides and immune checkpoint protein expression in cancer cells with broad mechanistic and clinical implications.
Topics & Concepts
Gene knockdownOuabainCardiac glycosideDownregulation and upregulationChemistryImmune checkpointKynurenineCancer cellCancer researchImmune systemDigoxinCell biologyTryptophanBiochemistryBiologyInternal medicineCancerMedicineImmunotherapyImmunologyAmino acidGeneOrganic chemistryApoptosisHeart failureSodiumTryptophan and brain disordersBipolar Disorder and TreatmentElectrolyte and hormonal disorders