Faculty Collaboration Database

Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in Kras^G12D-driven tumors. EMBO Mol Med 2024 Mar;16(3):475-505

Date

02/16/2024

Pubmed ID

38360999

Pubmed Central ID

PMC10940650

DOI

10.1038/s44321-024-00032-2

Scopus ID

2-s2.0-85185320484 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

We find that NUPR1, a stress-associated intrinsically disordered protein, induced droplet formation via liquid-liquid phase separation (LLPS). NUPR1-driven LLPS was crucial for the creation of NUPR1-dependent stress granules (SGs) in pancreatic cancer cells since genetic or pharmacological inhibition by ZZW-115 of NUPR1 activity impeded SGs formation. The Kras^G12D mutation induced oncogenic stress, NUPR1 overexpression, and promoted SGs development. Notably, enforced NUPR1 expression induced SGs formation independently of mutated Kras^G12D. Mechanistically, Kras^G12D expression strengthened sensitivity to NUPR1 inactivation, inducing cell death, activating caspase 3 and releasing LDH. Remarkably, ZZW-115-mediated SG-formation inhibition hampered the development of pancreatic intraepithelial neoplasia (PanINs) in Pdx1-cre;LSL-Kras^G12D (KC) mice. ZZW-115-treatment of KC mice triggered caspase 3 activation, DNA fragmentation, and formation of the apoptotic bodies, leading to cell death, specifically in Kras^G12D-expressing cells. We further demonstrated that, in developed PanINs, short-term ZZW-115 treatment prevented NUPR1-associated SGs presence. Lastly, a four-week ZZW-115 treatment significantly reduced the number and size of PanINs in KC mice. This study proposes that targeting NUPR1-dependent SGs formation could be a therapeutic approach to induce cell death in Kras^G12D-dependent tumors.

Author List

Santofimia-Castaño P, Fraunhoffer N, Liu X, Bessone IF, di Magliano MP, Audebert S, Camoin L, Estaras M, Brenière M, Modesti M, Lomberk G, Urrutia R, 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

Animals
Carcinoma in Situ
Carcinoma, Pancreatic Ductal
Caspase 3
Mice
Pancreatic Neoplasms
Piperazines
Proto-Oncogene Proteins p21(ras)
Synthetic Lethal Mutations
Thiazines