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Targeting of p53 and its homolog p73 by protoporphyrin IX
Alicja Sznarkowska1, Katarzyna Maleńczyk, Leszek Kadziński
1Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk & Medical University of Gdansk, Gdansk, Poland.
Abstract:
The p53 tumor suppressor is recognized as a promising target for anti-cancer therapies. We previously reported that protoporphyrin IX (PpIX) disrupts the p53/murine double minute 2 (MDM2) complex and leads to p53 accumulation and activation of apoptosis in HCT 116 cells. Here we show the direct binding of PpIX to the N-terminal domain of p53. Furthermore, we addressed the induction of apoptosis in HCT 116 p53-null cells by PpIX and revealed interactions between PpIX and p73. We propose that PpIX disrupts the p53/MDM2 or MDMX and p73/MDM2 complexes and thereby activates the p53- or p73-dependent cancer cell death.
Insights
Protoporphyrin IX (PpIX) binds directly to the p53 tumor suppressor, disrupting key protein complexes. This mechanism activates p53 or p73, leading to cancer cell death and offering a novel anti-cancer therapy target.
Area of Science:
- Molecular biology
- Cancer research
- Drug discovery
Background:
- The p53 tumor suppressor is a critical target for anti-cancer drug development.
- Previous studies indicated protoporphyrin IX (PpIX) disrupts the p53/murine double minute 2 (MDM2) complex, inducing apoptosis in HCT 116 cells.
Purpose of the Study:
- To elucidate the direct binding interaction between PpIX and the p53 protein.
- To investigate PpIX-induced apoptosis in p53-null cells and its interaction with p73.
- To propose a mechanism for PpIX-mediated cancer cell death.
Main Methods:
- Direct binding assays to confirm PpIX interaction with the N-terminal domain of p53.
- Apoptosis induction studies in HCT 116 p53-null cells treated with PpIX.
- Analysis of PpIX interactions with p73.
Main Results:
- Demonstrated direct binding of PpIX to the N-terminal domain of p53.
- Confirmed PpIX-induced apoptosis in HCT 116 cells lacking p53.
- Identified interactions between PpIX and p73.
Conclusions:
- PpIX directly binds to p53, disrupting p53/MDM2 and p53/MDMX complexes.
- PpIX also interacts with p73, potentially disrupting p73/MDM2 complexes.
- PpIX activates cancer cell death through p53- or p73-dependent pathways, highlighting its therapeutic potential.
