Article
Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans
Free Radical Biology and Medicine
(2014)
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 con
fi
rmed
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 signi
fi
cantly 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 transcrip-
tional 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.
Disciplines
Publication Date
2014
DOI
10.1016/j.freeradbiomed.2013.10.003
Citation Information
Stapelberg, M., Zobalova, R., Nguyen, M., Walker, T., Stantic, M., Jacob, G., Pasdar, E., Thai, T., Prokopova, K., Yan, B., et al. (2014). Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans. Free Radical Biology and Medicine, 67, 41-50. DOI: 10.1016/j.freeradbiomed.2013.10.003