2. Academic Validation
  3. Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma

Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma

  • Cells. 2019 Nov 17;8(11):1453. doi: 10.3390/cells8111453.
Patricia Santofimia-Castaño 1 2,  Yi Xia 3,  Ling Peng 4,  Adrián Velázquez-Campoy 5 6 7 8 9,  Olga Abián 5 6 7 8 10,  Wenjun Lan 1 2,  Gwen Lomberk 11,  Raul Urrutia 11,  Bruno Rizzuti 12,  Philippe Soubeyran 1 2,  José Luis Neira 5 13,  Juan Iovanna 1 2
Affiliations

Affiliations

  • 1 Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université, CEDEX, Marseille 13288, France.
  • 2 Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, CEDEX, Marseille 13288, France.
  • 3 Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
  • 4 Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, «Equipe Labellisée Ligue Contre le Cancer», Parc Scientifique et Technologique de Luminy, CEDEX, Marseille 13288, France.
  • 5 Instituto de Biocomputación y Física de Sistemas Complejos, Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza 50009, Spain.
  • 6 Aragon Institute for Health Research (IIS Aragon), Universidad de Zaragoza, Zaragoza 50009, Spain.
  • 7 Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid 28029, Spain.
  • 8 Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza 50009, Spain.
  • 9 Fundacion ARAID, Government of Aragon, Universidad de Zaragoza, Zaragoza 50018, Spain.
  • 10 Instituto Aragonés de Ciencias de la Salud (IACS), Universidad de Zaragoza, Zaragoza 50009, Spain.
  • 11 Division of Research, Department of Surgery and the Genomic Sciences and Precision Medicine Center (GSPMC), Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • 12 CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, Cosenza 87036, Italy.
  • 13 Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Edificio Torregaitán, Elche 03202, Alicante, Spain.
PMID: 31744261 DOI: 10.3390/cells8111453
Abstract

Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the stress-induced nuclear protein 1 (NUPR1 ) belong to the most conserved ones. NUPR1 is an 82-residue-long, monomeric, basic and intrinsically disordered protein (IDP), which was found to be invariably overexpressed in some, if not all, Cancer tissues. Remarkably, we and Others have previously showed that genetic inactivation of the Nupr1 gene antagonizes the growth of pancreatic Cancer as well as several other tumors. With the use of a multidisciplinary strategy by combining biophysical, biochemical, bioinformatic, and biological approaches, a trifluoperazine-derived compound, named ZZW-115, has been identified as an inhibitor of the NUPR1 functions. The Anticancer activity of the ZZW-115 was first validated on a large panel of Cancer cells. Furthermore, ZZW-115 produced a dose-dependent tumor regression of the tumor size in xenografted mice. Mechanistically, we have demonstrated that NUPR1 binds to several importins. Because ZZW-115 binds NUPR1 through the region around the amino acid Thr68, which is located into the nuclear location signal (NLS) region of the protein, we demonstrated that treatment with ZZW-115 inhibits completely the translocation of NUPR1 from the cytoplasm to the nucleus by competing with importins.

Keywords

NUPR1; drug design; intrinsically disordered protein; molecular dynamics; pancreatic ductal adenocarcinoma; spectroscopy; stress response.

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