Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma.

Cells
Patricia Santofimia-CastañoJuan L Iovanna

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 prot...Continue Reading

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Citations

Jan 2, 2021·International Journal of Biological Macromolecules·Patricia Santofimia-CastañoJosé L Neira
Jan 30, 2021·Nature Communications·Jiao LiuDaolin Tang
Feb 1, 2021·Pancreatology : Official Journal of the International Association of Pancreatology (IAP) ... [et Al.]·Patricia Santofimia-Castaño, Juan Iovanna
Jun 13, 2020·Trends in Cancer·Yuwen LiGuoyu Meng
Apr 2, 2021·The Journal of Pharmacy and Pharmacology·Lei JiangZhensheng Qin
Jun 9, 2021·The Biochemical Journal·Kaare TeilumBirthe B Kragelund
Oct 3, 2021·Cell Death Discovery·Can HuangJuan Iovanna

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Datasets Mentioned

BETA
MDA-MB-231

Methods Mentioned

BETA
antisense oligonucleotide
isothermal
NMR
xenografts
circular dichroism
Nuclear Translocation

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