Abstract
Cancers cells shift their metabolism towards glycolysis in order to help them support the biosynthetic demands necessary to sustain cell proliferation and growth, adapt to stress and avoid excessive reactive oxygen species (ROS) accumulation. While the p53 tumor suppressor protein is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism. TIGAR is a p53 target that functions as a fructose-2,6-bisphosphatase, thereby lowering glycolytic flux and promoting antioxidant functions. By protecting cells from oxidative stress, TIGAR may mediate some of the tumor suppressor activity of p53 but could also contribute to tumorigenesis. Here we discuss the activities of TIGAR described so far, and the potential consequences of TIGAR expression on normal and tumor cells.
Highlights
Cellular metabolism is a highly regulated process through which cell growth and survival are maintained
P53 plays a role in preserving mitochondrial health with several activities likely to contribute to the maintenance of mitochondrial integrity. These include the induction of genes such as the ribonucleotide reductase subunit p53R2 [45,46,47], whose activity is required for the stability of mitochondrial DNA and the ability of p53 to contribute to the removal of damaged mitochondria [48,49]. While these results suggest that p53 helps to maintain mitochondrial quality, other studies have demonstrated a role for p53 in the inhibition of mitophagy, an effect that would lead to increased mitochondrial dysfunction [50,51,52]
While TP53-induced glycolysis and apoptosis regulator (TIGAR) is induced during the early stages of a p53 response, a fall in TIGAR protein levels was shown to accompany the switch to apoptosis in cells under persistent p53-activating stress [55]. These results suggest that TIGAR levels must be tightly regulated during a p53 response, and there is growing evidence that the deregulated expression of TIGAR may contribute to cancer development
Summary
Cellular metabolism is a highly regulated process through which cell growth and survival are maintained. PFKFB4 shows predominantly bisphosphatase activity, leading to the suggestion that these cancer cells rely on PFKFB4 to dampen glycolytic flux, promote the PPP and manage ROS accumulation very similar to the proposed action of TIGAR This response to PFKFB4 expression may be more complicated than functioning to inhibit the PFK-1 step in glycolysis. While the inhibition of PFK-1 activity through glycosylation has been shown to promote the PPP and growth of cancer cells [66], loss of FBP1, whose activity directly opposes that of PFK-1 by converting F-1,6-P2 to F-6-P, has been observed in human liver, colon, gastric and breast cancers [90,91] In this context, FBP1 expression is associated with decreased glycolysis and enhanced flux through the TCA cycle, and with decreased PPP flux, and thereby an increase in ROS [92]. There is still much to be learnt about how TIGAR expression and activity are controlled under normal as well as stressed conditions
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