title: Novel p53-dependent anticancer strategy by targeting iron signaling and BNIP3L-induced mitophagy.
abstract: This study identifies BNIP3L as the key regulator of p53-dependent cell death mechanism in colon cancer cells targeted by the novel gallium based anticancer drug, KP46. KP46 specifically accumulated into mitochondria where it caused p53-dependent morphological and functional damage impairing mitochondrial dynamics and bioenergetics. Furthermore, competing with iron for cellular uptake, KP46 lowered the intracellular labile iron pools and intracellular heme. Accordingly, p53 accumulated in the nucleus where it activated its transcriptional target BNIP3L, a BH3 only domain protein with functions in apoptosis and mitophagy. Upregulated BNIP3L sensitized the mitochondrial permeability transition and strongly induced PARKIN-mediated mitochondrial clearance and cellular vacuolization. Downregulation of BNIP3L entirely rescued cell viability caused by exposure of KP46 for 24 hours, confirming that early induced cell death was regulated by BNIP3L. Altogether, targeting BNIP3L in wild-type p53 colon cancer cells is a novel anticancer strategy activating iron depletion signaling and the mitophagy-related cell death pathway.
authors.affiliation: Department of Internal Medicine I, Medical University Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Nastasia
authors.initials: N
authors.lastname: Wilfinger
authors.affiliation: Department of Internal Medicine I, Medical University Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Shane
authors.initials: S
authors.lastname: Austin
authors.affiliation: Department of Medical Chemistry, Medical University of Vienna, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Scheiber-Mojdehkar
authors.affiliation: Department of Internal Medicine I, Medical University Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Cell Imaging and Ultrastructure Research, University of Vienna, Vienna, Austria.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Reipert
authors.affiliation: Department of Medical Chemistry, Medical University of Vienna, Vienna, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Praschberger
authors.affiliation: Department of Internal Medicine I, Medical University Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Jakob
authors.initials: J
authors.lastname: Paur
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Trondl
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.affiliation: Department of Internal Medicine I, Medical University Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Christoph C
authors.initials: CC
authors.lastname: Zielinski
authors.affiliation: Department of Internal Medicine I, Medical University Vienna, Vienna, Austria.|Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Nowikovsky
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005708:Gallium / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D063306:Mitophagy / Q000187:drug effects* / Q000235:genetics; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D015125:Oxyquinoline / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C116838:BNIP3L protein, human; D008565:Membrane Proteins; D009942:Organometallic Compounds; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C408502:tris(8-quinolinolato)gallium (III); D015125:Oxyquinoline; D005708:Gallium; D007501:Iron; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: BNIP3L; cancer; gallium complex; mitophagy; p53