Abstract
The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein-1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II and IV subunits, dampened reactive oxygen species production, and enabled oxidative bioenergetics in tumor cells. Of note, we found that genetic or pharmacological targeting of this pathway shuts off tumor cell motility and invasion, kills Myc-expressing cells in a TRAP1-dependent manner, and suppresses primary and metastatic tumor growth in vivo We conclude that exploitation of mitochondrial functions is a general trait of tumorigenesis and that this reliance of cancer cells on mitochondrial OXPHOS pathways could offer an actionable therapeutic target in the clinic.
Highlights
The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown
The Myc target gene(s) in tumor progression has not been completely elucidated, and controversy still exists about the requirements of Myc-directed gene expression [12], this pathway connects to multiple aspects of tumor metabolism [13], including mitochondrial functions [14, 15]
Much work has been devoted to the preferential utilization of glycolysis by tumor cells, even when oxygen is present [2], and its impact on cancer progression [3]
Summary
A hallmark of cancer is the reprogramming of cellular metabolism [1]. Much work has been devoted to the preferential utilization of glycolysis by tumor cells, even when oxygen is present [2], and its impact on cancer progression [3]. A second focused metabolomics screen of ϳ300 metabolites gave similar results (Fig. S1B), as Myc silencing in PC3 cells reduced the levels of oxidative phosphorylation and TCA cycle biochemicals, along with metabolites involved in purine and pyrimidine biosynthetic pathways and amino acid levels (Fig. 1A and Fig. S1B). Myc knockdown did not affect glutamine levels in PC3 cells [13], suggesting tumor-specific differences in metabolic reprogramming. Consistent with these data, Myc-silenced PC3 cells exhibited decreased oxygen consumption rates (OCR) (Fig. S1C) and overall reduced oxygen consumption (Fig. 1B). Together with lower glucose utilization (Fig. S1D), decreased lactate generation (Fig. S1E), and reduced extracellular acidification rates (ECAR) (Fig. S1F), these cells showed diminished ATP production, compared with control transfectants (Fig. 1C)
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