Faculty Collaboration Database

Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma. Cells 2019 Nov 17;8(11)

Date

11/21/2019

Pubmed ID

31744261

Pubmed Central ID

PMC6912534

DOI

10.3390/cells8111453

Scopus ID

2-s2.0-85082729502 (requires institutional sign-in at Scopus site)   42 Citations

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.

Author List

Santofimia-Castaño P, Xia Y, Peng L, Velázquez-Campoy A, Abián O, Lan W, Lomberk G, Urrutia R, Rizzuti B, Soubeyran P, Neira JL, Iovanna J

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Basic Helix-Loop-Helix Transcription Factors
Dose-Response Relationship, Drug
Gene Expression Regulation, Neoplastic
Humans
Mice
Neoplasm Proteins
Pancreatic Neoplasms
Phenothiazines
Protein Transport
Xenograft Model Antitumor Assays