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Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells

Alicja Sznarkowska, Anna Kostecka, Anna Kawiak, Pilar Acedo, Mattia Lion, Alberto Inga, Joanna Zawacka-Pankau
doi: https://doi.org/10.1101/357293
Alicja Sznarkowska
Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland
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Anna Kostecka
Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland
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Anna Kawiak
Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Abrahama 58, 80-307 Gdansk, Poland
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Pilar Acedo
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Biomedicum, Solnavägen 9, 171 65, Stockholm, Sweden
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Mattia Lion
Centre for Integrative Biology, CIBIO, University of Trento, via Sommarive 9, 38123, Trento, Italy
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Alberto Inga
Centre for Integrative Biology, CIBIO, University of Trento, via Sommarive 9, 38123, Trento, Italy
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Joanna Zawacka-Pankau
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Biomedicum, Solnavägen 9, 171 65, Stockholm, Sweden
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  • For correspondence: joannazawackapankau1@gmail.com
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Abstract

Background The p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated ΔN isoform that inhibits TAp73 and p53 and thus, acts as an oncogene.

Results By employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid (ALA) applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch.

Conclusion Our findings may in future contribute to the successful repurposing of PpIX into clinical practice.

  • Abbreviations

    TA
    transcriptionally active
    PpIX
    protoporphyrin IX
    CDDP
    cisplatin
    CXH
    cycloheximide
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    Posted August 15, 2018.
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    Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells
    Alicja Sznarkowska, Anna Kostecka, Anna Kawiak, Pilar Acedo, Mattia Lion, Alberto Inga, Joanna Zawacka-Pankau
    bioRxiv 357293; doi: https://doi.org/10.1101/357293
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    Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, induces apoptosis in TP53-deficient cancer cells
    Alicja Sznarkowska, Anna Kostecka, Anna Kawiak, Pilar Acedo, Mattia Lion, Alberto Inga, Joanna Zawacka-Pankau
    bioRxiv 357293; doi: https://doi.org/10.1101/357293

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