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Figure 3. Transcriptional reprogramming of metabolism in cancer cells undergoing hypoxia and oxidative stress causes metastasis. The increased mitochondrial and cellular ROS (+) induced by intermittent hypoxia in cancer cells causes metabolic reprogramming. Expression levels and activation of key redox regulatory proteins: p53, PGC1α, HIF-1α, KEAP1, NRF2 and ARF leads to increased antioxidant gene expression and restoration of redox homeostasis. However, the outcome will depend on factors such as the mutational status of the genes encoding these redox regulators and resulting imbalances in their activity with potential to promote increased invasiveness, migration, OxPhos and metastasis. It is uncertain what levels of mitochondria will exist inside metastatic cells and will depend on the level of the PGC1α/NRF1/TFAM axis represented by the symbol “?” and the bidirectional arrow. The reprogramming into metastatic cancer cells is driven by NRF2, mut-p53 and HIF-1α which are critical metastatic biomarkers. HIF: hypoxia-induced factor; NRF: nuclear respiratory factor; GSH: reduced glutathione; ROS: reactive oxygen species; TFAM: mitochondrial transcription factor A; PGC1α: peroxisome proliferator-activated receptor gamma coactivator 1-alpha; KEAP1: Kelch-like ECH associated protein1; NRF: nuclear respiratory factor; γ-ECS: gamma-glutamylcysteine synthetase; Trx: thioredoxin; TrxR: thioredoxin reductase