Mitocans target tryptophan metabolism to remove the mimicry of tumour-initiating cells

Following therapy, tumour-initiating cells (TICs) survive and give rise to second-line tumours. Gene set enrichment analysis of microarray data and microRNA analysis confirmed the validity of spheroid cultures as models of TICs for breast and prostate cancer and mesothelioma cell lines. Pathway analysis revealed increased Trp metabolism in all types of TICs with indoleamine 2,3-dioxygenase (IDO) as the rate-limiting enzyme. TICs also expressed higher levels of the Trp uptake system consisting of CD98 and LAT1 with functional consequences. Mitocans, represented by vitamin E (VE) analogues, suppressed IDO1 in TICs with functional mitochondrial complex II, a target for the agents. IDO1 expression was regulated via a mechanism involving both transcriptional and post-transcriptional mechanisms. IDO1 increase and its suppression by VE analogues were replicated in TICs from primary human glioblastomas. Our work points to Trp metabolism as a novel mechanism of TICs to bypass the immune surveillance and to VE analogues as agents that remove this ‘mimicry’. Total RNA obtained from from breast cancer (MCF7), mesothelioma (IstMes2) and prostate cancer (LNCaP) adherent cell lines was compared to their corresponding sphere cultures