000119744 001__ 119744
000119744 005__ 20240319081025.0
000119744 0247_ $$2doi$$a10.3390/cancers14163851
000119744 0248_ $$2sideral$$a130499
000119744 037__ $$aART-2022-130499
000119744 041__ $$aeng
000119744 100__ $$aSoler-Agesta, Ruth$$uUniversidad de Zaragoza
000119744 245__ $$aPT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies
000119744 260__ $$c2022
000119744 5060_ $$aAccess copy available to the general public$$fUnrestricted
000119744 5203_ $$aPT-112 is a novel pyrophosphate–platinum conjugate, with clinical activity reported in advanced pretreated solid tumors. While PT-112 has been shown to induce robust immunogenic cell death (ICD) in vivo but only minimally bind DNA, the molecular mechanism underlying PT-112 target disruption in cancer cells is still under elucidation. The murine L929 in vitro system was used to test whether differential metabolic status alters PT-112’s effects, including cell cytotoxicity. The results showed that tumor cells presenting mutations in mitochondrial DNA (mtDNA) (L929dt and L929dt cybrid cells) and reliant on glycolysis for survival were more sensitive to cell death induced by PT-112 compared to the parental and cybrid cells with an intact oxidative phosphorylation (OXPHOS) pathway (L929 and dtL929 cybrid cells). The type of cell death induced by PT-112 did not follow the classical apoptotic pathway: the general caspase inhibitor Z-VAD-fmk did not inhibit PT-112-induced cell death, alone or in combination with the necroptosis inhibitor necrostatin-1. Interestingly, PT-112 initiated autophagy in all cell lines, though this process was not complete. Autophagy is known to be associated with an integrated stress response in cancer cells and with subsequent ICD. PT-112 also induced a massive accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial polarization—only in the sensitive cells harboring mitochondrial dysfunction—along with calreticulin cell-surface exposure consistent with ICD. PT-112 substantially reduced the amount of mitochondrial CoQ10 in L929 cells, while the basal CoQ10 levels were below our detection limits in L929dt cells, suggesting a potential relationship between a low basal level of CoQ10 and PT-112 sensitivity. Finally, the expression of HIF-1α was much higher in cells sensitive to PT-112 compared to cells with an intact OXPHOS pathway, suggesting potential clinical applications.
000119744 536__ $$9info:eu-repo/grantAgreement/ES/MICINN/PID2019-105128RB-I00
000119744 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000119744 590__ $$a5.2$$b2022
000119744 592__ $$a1.312$$b2022
000119744 591__ $$aONCOLOGY$$b72 / 241 = 0.299$$c2022$$dQ2$$eT1
000119744 593__ $$aOncology$$c2022$$dQ1
000119744 593__ $$aCancer Research$$c2022$$dQ2
000119744 594__ $$a7.4$$b2022
000119744 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000119744 700__ $$aMarco-Brualla, Joaquín$$uUniversidad de Zaragoza
000119744 700__ $$0(orcid)0000-0001-7947-8813$$aMinjárez-Sáenz, Martha$$uUniversidad de Zaragoza
000119744 700__ $$aYim, Christina Y.
000119744 700__ $$0(orcid)0000-0001-9047-0046$$aMartínez-Júlvez, Marta$$uUniversidad de Zaragoza
000119744 700__ $$aPrice, Matthew R.
000119744 700__ $$0(orcid)0000-0002-6600-1618$$aMoreno-Loshuertos, Raquel$$uUniversidad de Zaragoza
000119744 700__ $$aAmes, Tyler D.
000119744 700__ $$aJimeno, José
000119744 700__ $$0(orcid)0000-0002-5175-8394$$aAnel, Alberto$$uUniversidad de Zaragoza
000119744 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000119744 773__ $$g14, 16 (2022), 3851 [21 pp. ]$$pCancers$$tCancers$$x2072-6694
000119744 8564_ $$s4268399$$uhttps://zaguan.unizar.es/record/119744/files/texto_completo.pdf$$yVersión publicada
000119744 8564_ $$s2824510$$uhttps://zaguan.unizar.es/record/119744/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000119744 909CO $$ooai:zaguan.unizar.es:119744$$particulos$$pdriver
000119744 951__ $$a2024-03-18-16:37:35
000119744 980__ $$aARTICLE