Increased 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.
Chicago Sky Blue
FLAD1
PDAC
cancer stem cells
flavoenzymes
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
31
03
2023
received:
13
01
2023
accepted:
30
05
2023
medline:
23
10
2023
pubmed:
31
5
2023
entrez:
31
5
2023
Statut:
ppublish
Résumé
FLAD1, 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 (IC
Substances chimiques
Tumor Suppressor Protein p53
0
pontamine sky blue
2610-05-1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4679-4694Informations de copyright
© 2023 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
Lambert A, Conroy T & Ducreux M (2021) Future directions in drug development in pancreatic cancer. Semin Oncol 48, 47-56.
Tanabe A & Sahara H (2020) The metabolic heterogeneity and flexibility of cancer stem cells. Cancer 12, 2780.
Feng Z, Shi M, Li K, Ma Y, Jiang L, Chen H & Peng C (2020) Development and validation of a cancer stem cell-related signature for prognostic prediction in pancreatic ductal adenocarcinoma. J Transl Med 18, 360.
Leone A, Roca MS, Ciardiello C, Costantini S & Budillon A (2017) Oxidative stress gene expression profile correlates with cancer patient poor prognosis: identification of crucial pathways might select novel therapeutic approaches. Oxid Med Cell Longev 2017, 2597581.
Barile M, Giancaspero TA, Leone P, Galluccio M & Indiveri C (2016) Riboflavin transport and metabolism in humans. J Inherit Metab Dis 39, 545-557.
Olsen RKJ, Konarikova E, Giancaspero TA, Mosegaard S, Boczonadi V, Matakovic L, Veauville-Merllie A, Terrile C, Schwarzmayr T, Haack TB et al. (2016) Riboflavin-responsive and -non-responsive mutations in FAD synthase cause multiple acyl-CoA dehydrogenase and combined respiratory-chain deficiency. Am J Hum Genet 98, 1130-1145.
Giancaspero TA, Busco G, Panebianco C, Carmone C, Miccolis A, Liuzzi GM, Colella M & Barile M (2013) FAD synthesis and degradation in the nucleus create a local flavin cofactor pool. J Biol Chem 288, 29069-29080.
Giancaspero TA, Colella M, Brizio C, Difonzo G, Fiorino GM, Leone P, Brandsch R, Bonomi F, Iametti S & Barile M (2015) Remaining challenges in cellular flavin cofactor homeostasis and flavoprotein biogenesis. Front Chem 3, 30.
Torchetti EM, Brizio C, Colella M, Galluccio M, Giancaspero TA, Indiveri C, Roberti M & Barile M (2010) Mitochondrial localization of human FAD synthetase isoform 1. Mitochondrion 10, 263-273.
Brizio C, Galluccio M, Wait R, Torchetti EM, Bafunno V, Accardi R, Gianazza E, Indiveri C & Barile M (2006) Over-expression in Escherichia coli and characterization of two recombinant isoforms of human FAD synthetase. Biochem Biophys Res Commun 344, 1008-1016.
Leone P, Galluccio M, Brizio C, Barbiroli A, Iametti S, Indiveri C & Barile M (2019) The hidden side of the human FAD synthase 2. Int J Biol Macromol 138, 986-995.
Miccolis A, Galluccio M, Giancaspero TA, Indiveri C & Barile M (2012) Bacterial over-expression and purification of the 3'phosphoadenosine 5'phosphosulfate (PAPS) reductase domain of human FAD synthase: functional characterization and homology modeling. Int J Mol Sci 13, 16880-16898.
Leone P, Galluccio M, Barbiroli A, Eberini I, Tolomeo M, Vrenna F, Gianazza E, Iametti S, Bonomi F, Indiveri C et al. (2018) Bacterial production, characterization and protein modeling of a novel monofuctional isoform of FAD synthase in humans: an emergency protein? Molecules 23, 116.
Powers HJ (2003) Riboflavin (vitamin B-2) and health. Am J Clin Nutr 77, 1352-1360.
Eli M, Li DS, Zhang WW, Kong B, Du CS, Wumar M, Mamtimin B, Sheyhidin I & Hasim A (2012) Decreased blood riboflavin levels are correlated with defective expression of RFT2 gene in gastric cancer. World J Gastroenterol 18, 3112-3118.
Fu T, Liu Y, Wang Q, Sun Z, Di H, Fan W, Liu M & Wang J (2016) Overexpression of riboflavin transporter 2 contributes toward progression and invasion of glioma. Neuroreport 27, 1167-1173.
Long L, Pang XX, Lei F, Zhang JS, Wang W, Liao LD, Xu XE, He JZ, Wu JY, Wu ZY et al. (2018) SLC52A3 expression is activated by NF-kappaB p65/Rel-B and serves as a prognostic biomarker in esophageal cancer. Cell Mol Life Sci 75, 2643-2661.
Aili A, Hasim A, Kelimu A, Guo X, Mamtimin B, Abudula A & Upur H (2013) Association of the plasma and tissue riboflavin levels with C20orf54 expression in cervical lesions and its relationship to HPV16 infection. PLoS One 8, e79937.
Bartmann L, Schumacher D, von Stillfried S, Sternkopf M, Alampour-Rajabi S, van Zandvoort M, Kiessling F & Wu Z (2019) Evaluation of riboflavin transporters as targets for drug delivery and Theranostics. Front Pharmacol 10, 79.
Tutino V, Defrancesco ML, Tolomeo M, De Nunzio V, Lorusso D, Paleni D, Caruso MG, Notarnicola M & Barile M (2018) The expression of riboflavin transporters in human colorectal cancer. Anticancer Res 38, 2659-2667.
Hu P, Pan Y, Wang C, Zhang W, Huang H, Wang J & Zhang N (2020) FLAD1 is up-regulated in gastric cancer and is a potential prediction of prognosis. Int J Med Sci 17, 1763-1772.
Mei M, Song W, Wang Y & Zhang M (2021) Significant diagnostic and prognostic value of FLAD1 and related MicroRNAs in breast cancer after a Pan-cancer analysis. Dis Markers 2021, 6962526.
Stein Y, Rotter V & Aloni-Grinstein R (2019) Gain-of-function mutant p53: all the roads Lead to tumorigenesis. Int J Mol Sci 20, 6197.
Ouyang H, Mou L, Luk C, Liu N, Karaskova J, Squire J & Tsao MS (2000) Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype. Am J Pathol 157, 1623-1631.
Jin K, Zheng L, Ye L, Xie Z, Gao J, Lou C, Pan W, Pan B, Liu S, Chen Z et al. (2021) Chicago sky blue 6B (CSB6B), an allosteric inhibitor of macrophage migration inhibitory factor (MIF), suppresses osteoclastogenesis and promotes osteogenesis through the inhibition of the NF-kappaB signaling pathway. Biochem Pharmacol 192, 114734.
Dalla Pozza E, Dando I, Biondani G, Brandi J, Costanzo C, Zoratti E, Fassan M, Boschi F, Melisi D, Cecconi D et al. (2015) Pancreatic ductal adenocarcinoma cell lines display a plastic ability to bi-directionally convert into cancer stem cells. Int J Oncol 46, 1099-1108.
Biondani G, Zeeberg K, Greco MR, Cannone S, Dando I, Dalla Pozza E, Mastrodonato M, Forciniti S, Casavola V, Palmieri M et al. (2018) Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome. FEBS J 285, 2104-2124.
Kim HJ & Winge DR (2013) Emerging concepts in the flavinylation of succinate dehydrogenase. Biochim Biophys Acta 1827, 627-636.
Fabian A, Stegner S, Miarka L, Zimmermann J, Lenk L, Rahn S, Buttlar J, Viol F, Knaack H, Esser D et al. (2019) Metastasis of pancreatic cancer: an uninflamed liver micromilieu controls cell growth and cancer stem cell properties by oxidative phosphorylation in pancreatic ductal epithelial cells. Cancer Lett 453, 95-106.
Brizio C, Brandsch R, Bufano D, Pochini L, Indiveri C & Barile M (2004) Over-expression in Escherichia coli, functional characterization and refolding of rat dimethylglycine dehydrogenase. Protein Expr Purif 37, 434-442.
Giancaspero TA, Wait R, Boles E & Barile M (2008) Succinate dehydrogenase flavoprotein subunit expression in Saccharomyces cerevisiae-involvement of the mitochondrial FAD transporter, Flx1p. FEBS J 275, 1103-1117.
Sharma P, Maklashina E, Cecchini G & Iverson TM (2020) The roles of SDHAF2 and dicarboxylate in covalent flavinylation of SDHA, the human complex II flavoprotein. Proc Natl Acad Sci USA 117, 23548-23556.
Dong J, Pervaiz W, Tayyab B, Li D, Kang L, Zhang H, Gong H, Ma X, Li J, Agboyibor C et al. (2022) A comprehensive comparative study on LSD1 in different cancers and tumor specific LSD1 inhibitors. Eur J Med Chem 240, 114564.
Hosseini A & Minucci S (2017) A comprehensive review of lysine-specific demethylase 1 and its roles in cancer. Epigenomics 9, 1123-1142.
Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y, Mimasu S, Umehara T, Yokoyama S, Kosai K & Nakao M (2012) FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat Commun 3, 758.
Leone P, Tolomeo M & Barile M (2021) Continuous and discontinuous approaches to study FAD synthesis and degradation catalyzed by purified recombinant FAD synthase or cellular fractions. Methods Mol Biol 2280, 87-116.
Barile M, Brizio C, De Virgilio C, Delfine S, Quagliariello E & Passarella S (1997) Flavin adenine dinucleotide and flavin mononucleotide metabolism in rat liver-the occurrence of FAD pyrophosphatase and FMN phosphohydrolase in isolated mitochondria. Eur J Biochem 249, 777-785.
Torchetti EM, Bonomi F, Galluccio M, Gianazza E, Giancaspero TA, Iametti S, Indiveri C & Barile M (2011) Human FAD synthase (isoform 2): a component of the machinery that delivers FAD to apo-flavoproteins. FEBS J 278, 4434-4449.
Sebastian M, Anoz-Carbonell E, Gracia B, Cossio P, Ainsa JA, Lans I & Medina M (2018) Discovery of antimicrobial compounds targeting bacterial type FAD synthetases. J Enzyme Inhib Med Chem 33, 241-254.
Huerta C, Borek D, Machius M, Grishin NV & Zhang H (2009) Structure and mechanism of a eukaryotic FMN adenylyltransferase. J Mol Biol 389, 388-400.
Mantovani F, Collavin L & Del Sal G (2019) Mutant p53 as a guardian of the cancer cell. Cell Death Differ 26, 199-212.
Santoro V, Kovalenko I, Vriens K, Christen S, Bernthaler A, Haegebarth A, Fendt SM & Christian S (2020) SLC25A32 sustains cancer cell proliferation by regulating flavin adenine nucleotide (FAD) metabolism. Oncotarget 11, 801-812.
Muscogiuri G, Barrea L, Feola T, Gallo M, Messina E, Venneri MA, Faggiano A & Colao A (2020) Pancreatic neuroendocrine neoplasms: does sex matter? Trends Endocrinol Metab 31, 631-641.
Normand A, Riviere E & Renodon-Corniere A (2014) Identification and characterization of human Rad51 inhibitors by screening of an existing drug library. Biochem Pharmacol 91, 293-300.
Bakos E, Tusnady GE, Nemet O, Patik I, Magyar C, Nemeth K, Kele P & Ozvegy-Laczka C (2020) Synergistic transport of a fluorescent coumarin probe marks coumarins as pharmacological modulators of organic anion-transporting polypeptide, OATP3A1. Biochem Pharmacol 182, 114250.
Lipman BJ, Silverstein SC & Steinberg TH (1990) Organic anion transport in macrophage membrane vesicles. J Biol Chem 265, 2142-2147.
He Z, Yan L, Yong Z, Dong Z, Dong H & Gong Z (2013) Chicago sky blue 6B, a vesicular glutamate transporters inhibitor, attenuates methamphetamine-induced hyperactivity and behavioral sensitization in mice. Behav Brain Res 239, 172-176.
Arib C, Bouchemal N, Barile M, Paleni D, Djaker N, Dupont N & Spadavecchia J (2021) Flavin-adenine-dinucleotide gold complex nanoparticles: chemical modeling design, physico-chemical assessment and perspectives in nanomedicine. Nanoscale Adv 3, 6144-6156.
Huerta C, Grishin NV & Zhang H (2013) The “super mutant” of yeast FMN adenylyltransferase enhances the enzyme turnover rate by attenuating product inhibition. Biochemistry 52, 3615-3617.
Leone P, Galluccio M, Quarta S, Anoz-Carbonell E, Medina M, Indiveri C & Barile M (2019) Mutation of aspartate 238 in FAD synthase isoform 6 increases the specific activity by weakening the FAD binding. Int J Mol Sci 20, 6203.
Zeeberg K, Cardone RA, Greco MR, Saccomano M, Nohr-Nielsen A, Alves F, Pedersen SF & Reshkin SJ (2016) Assessment of different 3D culture systems to study tumor phenotype and chemosensitivity in pancreatic ductal adenocarcinoma. Int J Oncol 49, 243-252.
Tolomeo M, Chimienti G, Lanza M, Barbaro R, Nisco A, Latronico T, Leone P, Petrosillo G, Liuzzi GM, Ryder B et al. (2022) Retrograde response to mitochondrial dysfunctions associated to LOF variations in FLAD1 exon 2: unraveling the importance of RFVT2. Free Radic Res 56, 511-525.
Ryder B, Tolomeo M, Nochi Z, Colella M, Barile M, Olsen RK & Inbar-Feigenberg M (2019) A novel truncating FLAD1 variant, causing multiple acyl-CoA dehydrogenase deficiency (MADD) in an 8-year-old boy. JIMD Reports 45, 37-44.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS & Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30, 2785-2791.
Trott O & Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31, 455-461.
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC & Ferrin TE (2004) UCSF chimera-a visualization system for exploratory research and analysis. J Comput Chem 25, 1605-1612.