title: Cardiac Glycosides Activate the Tumor Suppressor and Viral Restriction Factor Promyelocytic Leukemia Protein (PML).
abstract: Cardiac glycosides (CGs), inhibitors of Na+/K+-ATPase (NKA), used clinically to treat heart failure, have garnered recent attention as potential anti-cancer and anti-viral agents. A high-throughput phenotypic screen designed to identify modulators of promyelocytic leukemia protein (PML) nuclear body (NB) formation revealed the CG gitoxigenin as a potent activator of PML. We demonstrate that multiple structurally distinct CGs activate the formation of PML NBs and induce PML protein SUMOylation in an NKA-dependent fashion. CG effects on PML occur at the post-transcriptional level, mechanistically distinct from previously described PML activators and are mediated through signaling events downstream of NKA. Curiously, genomic deletion of PML in human cancer cells failed to abrogate the cytotoxic effects of CGs and other apoptotic stimuli such as ceramide and arsenic trioxide that were previously shown to function through PML in mice. These findings suggest that alternative pathways can compensate for PML loss to mediate apoptosis in response to CGs and other apoptotic stimuli.
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: Snezana
authors.initials: S
authors.lastname: Milutinovic
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: Susanne
authors.initials: S
authors.lastname: Heynen-Genel
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chao
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: Antimone
authors.initials: A
authors.lastname: Dewing
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Solano
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: Loribelle
authors.initials: L
authors.lastname: Milan
authors.affiliation: Bemer USA, LLC, Carlsbad, CA, United States of America.
authors.forename: Nikki
authors.initials: N
authors.lastname: Barron
authors.affiliation: National Cancer Institute (NCI), Bethesda, MD, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: He
authors.affiliation: P.William Diaz, Pharmaceutical Consulting, Riverside, CA, United States of America.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Diaz
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, United States of America.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Hassig
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002301:Cardiac Glycosides / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D017353:Gene Deletion; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells
chemical_list: D002301:Cardiac Glycosides; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D000254:Sodium-Potassium-Exchanging ATPase