Novel p53-dependent anticancer strategy by targeting iron signaling and BNIP3L-induced mitophagy
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Nastasia Wilfinger1,2, Shane Austin1,2, Barbara Scheiber-Mojdehkar3, Walter Berger1,2, Siegfried Reipert4, Monika Praschberger3, Jakob Paur1,2, Robert Trondl5, Bernhard K. Keppler5, Christoph C. Zielinski1,2, Karin Nowikovsky1,2
1Department of Internal Medicine I, Medical University Vienna, Vienna, Austria
2Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
3Department of Medical Chemistry, Medical University of Vienna, Vienna, Austria
4Cell Imaging and Ultrastructure Research, University of Vienna, Vienna, Austria
5Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria
Karin Nowikovsky, e-mail: firstname.lastname@example.org
Keywords: cancer, p53, BNIP3L, mitophagy, gallium complex
Received: March 05, 2015 Accepted: September 26, 2015 Published: October 26, 2015
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.
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