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Published on: May 24, 2024
Targeting NUPR1 with the small compound ZZW-115 is an efficient strategy to treat hepatocellular carcinoma
Wenjun Lan1, Patricia Santofimia-Castaño2, Yi Xia3
1Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France; Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, «Equipe Labellisée Ligue Contre le Cancer», Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288, Marseille, France.
Abstract:
HCC is a highly lethal malignancy with Sorafenib as the only molecularly targeted drug. The multifunctional stress-associated protein, NUPR1, plays an essential role in controlling cell growth, migration, invasion and Sorafenib resistance in HCC. We report here that NUPR1 expression is absent in healthy liver and it is progressively upregulated in HCC premalignant lesions such as hepatitis and cirrhosis with a maximum expression in HCC samples, highlighting that NUPR1 is a potential drug target for HCC. We therefore assessed in this work, ZZW-115, a strong inhibitor of NUPR1, as a promising candidate for the treatment of HCC. We validated its extraordinary antitumor effect on HCC by using two HCC cell lines, HepG2-and Hep3B, both in cell based experiments and xenografted mice. We further revealed that ZZW-115 treatment induced cell death by apoptosis and necroptosis mechanisms, with a concomitant mitochondrial metabolism failure that triggers lower ATP production. Furthermore, the ATP depletion cannot be rescued by the apoptosis inhibitor Z-VAD-FMK and/or the necrosis inhibitor Necrostatin-1, indicating that ZZW-115 induces cell death through the mitochondrial failure.
Insights
NUPR1 protein promotes liver cancer (HCC) growth and Sorafenib resistance. A new drug, ZZW-115, inhibits NUPR1, effectively killing HCC cells by disrupting mitochondrial energy production.
Area of Science:
- Hepatology
- Oncology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is a deadly liver cancer with limited treatment options, Sorafenib being the sole targeted therapy.
- The stress-associated protein NUPR1 is upregulated in HCC and contributes to tumor progression and drug resistance.
- NUPR1 is absent in healthy liver tissue, increasing in premalignant conditions and peaking in HCC, suggesting it as a viable drug target.
Purpose of the Study:
- To investigate the potential of ZZW-115, a NUPR1 inhibitor, as a novel therapeutic agent for hepatocellular carcinoma (HCC).
- To elucidate the mechanisms underlying ZZW-115's anti-cancer effects in HCC models.
Main Methods:
- Utilized HepG2 and Hep3B HCC cell lines for in vitro experiments.
- Employed xenograft mouse models to assess in vivo efficacy.
- Analyzed cell death pathways (apoptosis, necroptosis) and mitochondrial function (ATP production).
Main Results:
- ZZW-115 demonstrated significant antitumor effects in both cell-based assays and mouse models.
- Treatment with ZZW-115 induced apoptosis and necroptosis in HCC cells.
- ZZW-115 caused mitochondrial dysfunction, leading to reduced ATP production, which was independent of apoptosis or necrosis inhibitors.
Conclusions:
- NUPR1 is a critical factor in HCC progression and Sorafenib resistance.
- ZZW-115 exhibits potent anti-HCC activity by targeting NUPR1.
- ZZW-115-induced cell death is mediated by mitochondrial metabolic failure, representing a novel therapeutic strategy for HCC.
