Novel p53-dependent anticancer strategy by targeting iron signaling and BNIP3L-induced mitophagy
| Autor: | Monika Praschberger, Bernhard K. Keppler, Shane Austin, Karin Nowikovsky, Siegfried Reipert, Barbara Scheiber-Mojdehkar, Walter Berger, Christoph C. Zielinski, Nastasia Wilfinger, Robert Trondl, Jakob Paur |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
p53 Programmed cell death Cell Survival Iron Ubiquitin-Protein Ligases gallium complex Blotting Western Antineoplastic Agents Apoptosis Gallium Mitochondrion Biology 03 medical and health sciences BNIP3L Gene Knockout Techniques Downregulation and upregulation Proto-Oncogene Proteins Mitophagy Organometallic Compounds cancer Humans Microscopy Confocal Reverse Transcriptase Polymerase Chain Reaction Tumor Suppressor Proteins Membrane Proteins HCT116 Cells Oxyquinoline Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology Oncology Mitochondrial permeability transition pore Colonic Neoplasms RNA Interference Signal transduction Tumor Suppressor Protein p53 Intracellular Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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