000162639 001__ 162639
000162639 005__ 20251017144631.0
000162639 0247_ $$2doi$$a10.1016/j.critrevonc.2025.104900
000162639 0248_ $$2sideral$$a145197
000162639 037__ $$aART-2025-145197
000162639 041__ $$aeng
000162639 100__ $$aIovanna, Juan
000162639 245__ $$aThe mitochondrial catastrophe induced by NUPR1 inhibitors as a novel strategy to fight against cancer
000162639 260__ $$c2025
000162639 5203_ $$aOver the past 25 years, the pivotal functions of the nuclear protein 1, NUPR1, have been described. NUPR1 is an intrinsically disordered stress protein whose expression is markedly upregulated under adverse conditions and in various cancers, particularly pancreatic ductal adenocarcinoma (PDAC). NUPR1 is essential for cellular survival by orchestrating responses to both extrinsic and intrinsic stressors, including oncogenic stress driven by mutations such as KRASG12D. Indeed, genetic studies have shown that inactivating NUPR1 effectively halts tumor growth, underscoring its promise as a therapeutic target. Applying a multidisciplinary approach, we identified the trifluoperazine-derived compound ZZW-115 with a remarkable efficacy. Treatment with ZZW-115 induces a mitochondrial catastrophe characterized by a mitochondrial hyperPARylation, with a shift in the utilization of glucose to glycolysis instead of oxidative phosphorylation (OXPHOS), which together with the Warburg effect, culminate in cellular glucose and energy collapse. This mitochondrial dysfunction triggers several cell death pathways, including apoptosis, necroptosis, and ferroptosis. In vivo studies have validated the antitumoral efficacy of ZZW-115, reinforcing its potential as a novel therapeutic strategy for cancers cells. The inactivation of NUPR1 via ZZW-115 represents an innovative therapeutic strategy by exploiting specific vulnerabilities in tumor cells. By inducing severe mitochondrial dysfunction and disrupting energy metabolism, this approach selectively eliminates cancer cells, opening new avenues for the treatment of aggressive tumors resistant to conventional therapies.
000162639 540__ $$9info:eu-repo/semantics/closedAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000162639 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000162639 700__ $$aNeira, José Luis
000162639 700__ $$0(orcid)0000-0001-5664-1729$$aAbian, Olga$$uUniversidad de Zaragoza
000162639 700__ $$0(orcid)0000-0001-5702-4538$$aVelázquez Campoy, Adrián$$uUniversidad de Zaragoza
000162639 700__ $$aXia, Yi
000162639 700__ $$aRizzuti, Bruno
000162639 700__ $$aPeng, Ling
000162639 700__ $$aLomberk, Gwen
000162639 700__ $$aUrrutia, Raul
000162639 700__ $$aSantofimia-Castaño, Patricia
000162639 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000162639 773__ $$g215 (2025), 104900 [7 pp.]$$pCrit. rev. oncol./hematol.$$tCRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY$$x1040-8428
000162639 8564_ $$s2299738$$uhttps://zaguan.unizar.es/record/162639/files/texto_completo.pdf$$yVersión publicada
000162639 8564_ $$s2226667$$uhttps://zaguan.unizar.es/record/162639/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000162639 909CO $$ooai:zaguan.unizar.es:162639$$particulos$$pdriver
000162639 951__ $$a2025-10-17-14:26:24
000162639 980__ $$aARTICLE