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: Nastasia Wilfinger, Shane Austin, Barbara Scheiber-Mojdehkar, Walter Berger, Siegfried Reipert, Monika Praschberger, Jakob Paur, Robert Trondl, Bernhard K Keppler, Christoph C Zielinski, Karin Nowikovsky
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 2 Pg. 1242-61 (Jan 12 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26517689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BNIP3L protein, human
• Membrane Proteins
• Organometallic Compounds
• Proto-Oncogene Proteins
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• tris(8-quinolinolato)gallium (III)
• Oxyquinoline
• Gallium
• Iron
• Ubiquitin-Protein Ligases
• parkin protein

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects, genetics)
• Blotting, Western
• Cell Survival (drug effects, genetics)
• Colonic Neoplasms (genetics, metabolism, pathology)
• Gallium (chemistry)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockout Techniques
• HCT116 Cells
• Humans
• Iron (metabolism)
• Membrane Proteins (genetics, metabolism)
• Microscopy, Confocal
• Mitophagy (drug effects, genetics)
• Organometallic Compounds (chemistry, pharmacology)
• Oxyquinoline (analogs & derivatives, chemistry, pharmacology)
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects, genetics)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)