Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans

Our plain-English summary of Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans, by M. Stapelberg, R. Zobalova, M.N. Nguyen, et al (Free Radical Biology & Medicine, 2014).

The study

• Authors: M. Stapelberg, R. Zobalova, M.N. Nguyen, T. Walker, M. Stantic, J. Goodwin, E.A. Pasdar, T. Thai, K. Prokopova, B. Yan, S. Hall, N. de Pennington, S.R. Thomas, G. Grant, J. Stursa, M. Bajzikova, A.C. Meedeniya, J. Truksa, S.J. Ralph, O. Ansorge, L.F. Dong, J. Neuzil
• Journal: Free Radical Biology & Medicine
• Published: 2014;67:41-50
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

© 2013 Elsevier Inc. All rights reserved.

In plain English

This laboratory study used cancer cells grown in dishes and in mice. It did not study asbestos exposure; it examined cells from patients, not the patients themselves. The authors grew breast cancer (MCF7), mesothelioma (IstMes2, epithelial type) and prostate cancer (LNCaP) cell lines, plus glioblastoma (brain tumor) cells from two patients. They grew these cells as floating 'spheres' to model tumor-initiating cells. Tryptophan metabolism was the only gene pathway increased in all three sphere types. In the three cell lines, messenger RNA for the enzyme IDO1 was about four- to sevenfold higher in spheres than in the same cells grown attached to the dish. All sphere types took up about two- to threefold more tryptophan. When mesothelioma sphere cells were passed through mice for four generations, IDO1 messenger RNA rose to about eightfold the first-generation level, and tumors appeared sooner each generation. Two experimental vitamin E-based compounds, alpha-tocopheryl succinate and MitoVES, lowered IDO1 in the spheres. The authors concluded that IDO1 is increased in these cells, possibly helping them escape the immune system, and that these compounds suppress it.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using cell cultures (adherent and sphere cultures as a model of tumor-initiating cells) and a mouse serial-transplantation experiment
• Who was studied: Cell lines MCF7 (breast cancer) and LNCaP (prostate cancer) from the ATCC. IstMes2 cells came from a mesothelioma patient (Torino University Hospital, Italy; epithelial histotype). Primary glioblastoma cells came from biopsies of two patients (B30 and B31, John Radcliffe Hospital, Oxford, UK). Balb/c nude mice were used for tumor transplantation
• Exposure: No asbestos exposure was studied. Sphere cells were treated with two mitocans for 3 and 6 hours: mitochondrially targeted vitamin E succinate (MitoVES), concentration printed as 5 mM, and alpha-tocopheryl succinate (alpha-TOS), concentration printed as 50 mM
• Main results:
  • Tryptophan (Trp) metabolism was the only pathway enhanced in all three types of sphere cells (MCF7, IstMes2, LNCaP)
  • For the three cell lines, IDO1 mRNA was about four- to sevenfold higher in spheres than in the matching adherent cells. IDO2 mRNA showed little or no change
  • Tryptophan in the culture medium fell by 3 (printed mg/ml) in 24 hours with sphere cells, compared with about 1 to 1.5 with adherent cells
  • Sphere cells made from the two patients' glioblastoma biopsies also showed increased IDO1 but not IDO2
  • Tryptophan uptake was about two- to threefold higher in all types of sphere cells examined
  • IstMes2 mesothelioma sphere cells were transplanted serially in nude mice. Tumors appeared sooner with each generation. IDO1 mRNA in the fourth generation was about eightfold higher than in the first, while IDO2 changed little
  • Both alpha-TOS and MitoVES strongly decreased IDO1 mRNA in sphere cells after 3 and 6 hours. The decrease in protein was less profound
  • MCF7 cells with silenced SDHC (a subunit of mitochondrial complex II) were resistant to the effect of MitoVES on IDO1
• The authors' conclusion: The authors concluded that model tumor-initiating cells from several unrelated cancer cell lines and from primary glioblastoma biopsies increase IDO1, which may allow long-term escape from immune surveillance. They also concluded that mitocans suppress IDO1 in these cells. They proposed that this may make the cells more vulnerable to immune cells, which they described as a subject of ongoing study
• Limitations the authors state:
  • The authors stated that further research is needed to confirm the proposed mechanism by which MitoVES acts on IDO1

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

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