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Updated: Sep 3, 2025
15:53
Cell Death Associated with Abnormal Mitosis Observed by Confocal Imaging in Live Cancer Cells
Published on: August 21, 2013
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NUPR1 protects against hyperPARylation-dependent cell death.
Patricia Santofimia-Castaño1, Can Huang1, Xi Liu1
1Centre de Recherche en Cancérologie de Marseille (CRCM), Parc Scientifique et Technologique de Luminy, INSERM U1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France.
Communications Biology
|July 22, 2022
Summary
The stress protein NUPR1 inhibits PARP1 activity. Its inactivation causes mitochondrial damage and cell death via a non-canonical Parthanatos pathway, offering new therapeutic targets for cancer.
Area of Science:
- Cellular Biology
- Molecular Biology
- Biochemistry
Background:
- The stress-associated protein NUPR1 plays a role in cellular responses.
- Poly(ADP-ribose) polymerase 1 (PARP1) is a key enzyme in DNA repair and cell death pathways.
Purpose of the Study:
- To investigate the interaction between NUPR1 and PARP1.
- To elucidate the role of NUPR1 in regulating PARP1 activity and its downstream effects on cell death.
- To explore potential therapeutic strategies targeting this pathway in cancer.
Main Methods:
- Proteomic, cellular, and biochemical analyses.
- In vitro assays to study protein-protein interactions and enzyme activity.
- Treatment with NUPR1 inhibitor (ZZW-115), PARP inhibitor (olaparib), PARG inhibitor (PDD00017273), and NAD+ precursor.
- Analysis of mitochondrial function, ROS production, and calcium levels.
Main Results:
- NUPR1 binds to PARP1 in the nucleus and inhibits its activity.
- NUPR1 inactivation or inhibition enhances 5-fluorouracil-induced PARylation and cell death.
- ZZW-115 treatment induces mitochondrial catastrophe, characterized by hyperPARylation, mitochondrial dysfunction, and increased ROS/Ca2+.
- Olaparib and nicotinamide mononucleotide rescue these effects, suggesting a role for NAD+ depletion and PARP hyperactivation.
Conclusions:
- NUPR1 inactivation triggers a non-canonical Parthanatos pathway, leading to mitochondrial catastrophe and cell death.
- Targeting the NUPR1-PARP1 interaction or downstream pathways presents a potential therapeutic strategy for pancreatic cancer.
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