Here, we show that new mitochondrial biogenesis is required for the anchorage independent survival and propagation of
cancer stem-like cells (CSCs). More specifically, we used the
drug XCT790 as an investigational tool, as it functions as a specific inhibitor of the ERRα-PGC1 signaling pathway, which governs mitochondrial biogenesis. Interestingly, our results directly demonstrate that
XCT790 efficiently blocks both the survival and propagation of
tumor initiating stem-like cells (
TICs), using the MCF7 cell line as a model system. Mechanistically, we show that
XCT790 suppresses the activity of several independent signaling pathways that are normally required for the survival of CSCs, such as Sonic hedgehog, TGFβ-SMAD, STAT3, and Wnt signaling. We also show that
XCT790 markedly reduces oxidative mitochondrial metabolism (OXPHOS) and that XCT790-mediated inhibition of CSC propagation can be prevented or reversed by
Acetyl-L-Carnitine (
ALCAR), a mitochondrial fuel. Consistent with our findings, over-expression of ERRα significantly enhances the efficiency of mammosphere formation, which can be blocked by treatment with mitochondrial inhibitors. Similarly, mammosphere formation augmented by FOXM1, a downstream target of Wnt/β-
catenin signaling, can also be blocked by treatment with three different classes of mitochondrial inhibitors (
XCT790,
oligomycin A, or
doxycycline). In this context, our unbiased proteomics analysis reveals that FOXM1 drives the expression of >90
protein targets associated with mitochondrial biogenesis, glycolysis, the EMT and
protein synthesis in MCF7 cells, processes which are characteristic of an anabolic CSC phenotype. Finally,
doxycycline is an FDA-approved
antibiotic, which is very well-tolerated in patients. As such,
doxycycline could be re-purposed clinically as a 'safe' mitochondrial inhibitor, to target FOXM1 and mitochondrial biogenesis in CSCs, to prevent
tumor recurrence and distant
metastasis, thereby avoiding patient relapse.