title: Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans.
abstract: Tumor-initiating cells (TICs) often survive therapy and give rise to second-line tumors. We tested the plausibility of sphere cultures as models of TICs. Microarray data and microRNA data analysis confirmed the validity of spheres as models of TICs for breast and prostate cancer as well as mesothelioma cell lines. Microarray data analysis revealed the Trp pathway as the only pathway upregulated significantly in all types of studied TICs, with increased levels of indoleamine-2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme of Trp metabolism along the kynurenine pathway. All types of TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. IDO1 expression was regulated via both transcriptional and posttranscriptional mechanisms, depending on the cancer type. Serial transplantation of TICs in mice resulted in gradually increased IDO1. Mitocans, represented by α-tocopheryl succinate and mitochondrially targeted vitamin E succinate (MitoVES), suppressed IDO1 in TICs. MitoVES suppressed IDO1 in TICs with functional mitochondrial complex II, involving transcriptional and posttranscriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work indicates that IDO1 is increased in TICs and that mitocans suppress the protein.
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia. Electronic address: pfm.stapelberg@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Stapelberg
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia; Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague 142 20, Czech Republic.
authors.forename: Renata
authors.initials: R
authors.lastname: Zobalova
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Maria Nga
authors.initials: MN
authors.lastname: Nguyen
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia; Department of Neurosurgery, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Walker
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Marina
authors.initials: M
authors.lastname: Stantic
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: Goodwin
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Elham Alizadeh
authors.initials: EA
authors.lastname: Pasdar
authors.affiliation: Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, 2052 NSW, Australia.
authors.forename: Thuan
authors.initials: T
authors.lastname: Thai
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague 142 20, Czech Republic; Faculty of Science, Charles University, 11000 Prague 1, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Prokopova
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: School of Pharmacy, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Hall
authors.affiliation: Department of Neurosurgery, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: de Pennington
authors.affiliation: Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, 2052 NSW, Australia.
authors.forename: Shane R
authors.initials: SR
authors.lastname: Thomas
authors.affiliation: School of Pharmacy, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Gary
authors.initials: G
authors.lastname: Grant
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia; Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague 160 00, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Stursa
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague 142 20, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Bajzikova
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Adrian C B
authors.initials: AC
authors.lastname: Meedeniya
authors.affiliation: Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague 142 20, Czech Republic.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Truksa
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ralph
authors.affiliation: Department of Neurosurgery, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia.
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Southport, 4222 QLD, Australia; Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague 142 20, Czech Republic. Electronic address: j.neuzil@griffith.edu.au.
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042963:Electron Transport Complex II / Q000235:genetics / Q000378:metabolism; D005260:Female; D027261:Fusion Regulatory Protein-1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014364:Tryptophan / Q000378:metabolism; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D027261:Fusion Regulatory Protein-1; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D027283:Large Neutral Amino Acid-Transporter 1; D007737:Kynurenine; D014364:Tryptophan; D042963:Electron Transport Complex II; D024502:alpha-Tocopherol
keywords: Free radicals; IDO; Mitocans; Mitochondrially targeted vitamin E succinate; Tumor-initiating cells