000126916 001__ 126916 000126916 005__ 20240731103328.0 000126916 0247_ $$2doi$$a10.1111/febs.16881 000126916 0248_ $$2sideral$$a134358 000126916 037__ $$aART-2023-134358 000126916 041__ $$aeng 000126916 100__ $$aNisco, Alessia 000126916 245__ $$aIncreased demand for FAD synthesis in differentiated and stem pancreatic cancer cells is accomplished by modulating FLAD1 gene expression: the inhibitory effect of Chicago Sky Blue 000126916 260__ $$c2023 000126916 5060_ $$aAccess copy available to the general public$$fUnrestricted 000126916 5203_ $$aFLAD1, along with its FAD synthase (FADS, EC 2.7.7.2) product, is crucial for flavin homeostasis and, due to its role in the mitochondrial respiratory chain and nuclear epigenetics, is closely related to cellular metabolism. Therefore, it is not surprising that it could be correlated with cancer. To our knowledge, no previous study has investigated FLAD1 prognostic significance in pancreatic ductal adenocarcinoma (PDAC). Thus, in the present work, the FAD synthesis process was evaluated in two PDAC cell lines: (a) PANC‐1‐ and PANC‐1‐derived cancer stem cells (CSCs), presenting the R273H mutation in the oncosuppressor p53, and (b) MiaPaca2 and MiaPaca2‐derived CSCs, presenting the R248W mutation in p53. As a control, HPDE cells expressing wt‐p53 were used. FADS expression/activity increase was found with malignancy and even more with stemness. An increased FAD synthesis rate in cancer cell lines is presumably demanded by the increase in the FAD‐dependent lysine demethylase 1 protein amount as well as by the increased expression levels of the flavoprotein subunit of complex II of the mitochondrial respiratory chain, namely succinate dehydrogenase. With the aim of proposing FADS as a novel target for cancer therapy, the inhibitory effect of Chicago Sky Blue on FADS enzymatic activity was tested on the recombinant 6His‐hFADS2 (IC50 = 1.2 μm) and PANC‐1‐derived CSCs' lysate (IC50 = 2–10 μm). This molecule was found effective in inhibiting the growth of PANC‐1 and even more of its derived CSC line, thus assessing its role as a potential chemotherapeutic drug. 000126916 536__ $$9info:eu-repo/grantAgreement/ES/MICINN-AEI/PID2019-103901GB-I00 000126916 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/ 000126916 590__ $$a5.5$$b2023 000126916 592__ $$a2.003$$b2023 000126916 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b58 / 313 = 0.185$$c2023$$dQ1$$eT1 000126916 593__ $$aBiochemistry$$c2023$$dQ1 000126916 593__ $$aMolecular Biology$$c2023$$dQ1 000126916 593__ $$aCell Biology$$c2023$$dQ1 000126916 594__ $$a11.7$$b2023 000126916 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000126916 700__ $$aCarvalho, Tiago M. A. 000126916 700__ $$aTolomeo, Maria 000126916 700__ $$aDi Molfetta, Daria 000126916 700__ $$aLeone, Piero 000126916 700__ $$aGalluccio, Michele 000126916 700__ $$0(orcid)0000-0001-8743-0182$$aMedina, Milagros$$uUniversidad de Zaragoza 000126916 700__ $$aIndiveri, Cesare 000126916 700__ $$aReshkin, Stephan Joel 000126916 700__ $$aCardone, Rosa Angela 000126916 700__ $$aBarile, Maria 000126916 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000126916 773__ $$g290, 19 (2023), 4679-4694$$pFEBS J.$$tFEBS Journal$$x1742-464X 000126916 8564_ $$s2855829$$uhttps://zaguan.unizar.es/record/126916/files/texto_completo.pdf$$yVersión publicada 000126916 8564_ $$s2258789$$uhttps://zaguan.unizar.es/record/126916/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000126916 909CO $$ooai:zaguan.unizar.es:126916$$particulos$$pdriver 000126916 951__ $$a2024-07-31-09:45:41 000126916 980__ $$aARTICLE