PTEN in cancer, metabolism, and aging

Abstract

Recent reports on mice with systemic overexpression of the tumor-suppressor PTEN (phosphatase and tensin homolog) have expanded our understanding of its physiological functions. Pten transgenic mice present increased energy expenditure, decreased adiposity, improved insulin sensitivity upon high-fat feeding or with aging, and extended lifespan. This has led to new mechanistic insights about the role of PTEN in metabolism. Interestingly, PTEN promotes oxidative phosphorylation and decreases glycolysis, thus preventing the metabolic reprogramming characteristic of cancer cells, which might be relevant to PTEN-mediated cancer protection. PTEN also upregulates UCP1 expression in brown adipocytes, which enhances their nutrient burning capacity and decreases adiposity and associated pathologies. The newly discovered effects of PTEN on metabolism open new avenues for exploration relevant to cancer, obesity, diabetes, and aging.

Figure 1. The PI3K/AKT pathway

Basic components of the PI3K/AKT pathway. PI3K is activated by numerous extracellular signals, most notably including insulin and IGF1, which act through their respective receptors and its associated proteins IRS1 and IRS1. Activation of PI3K generates the second messenger lipid PIP₃, which serves as an anchoring site for AKT and its ensuing activation. PTEN eliminates PIP₃, by converting it into PIP₂, thus counteracting the activity of PI3K. Among the main actions of AKT are the inhibition of the FOXO transcription factors, particularly FOXO1 and FOXO3, and the activation of the mTORC1 complex. The mTORC1 complex is characterized by the presence of mTOR, RAPTOR and mLST8 among other protein subunits. The kinases S6K1 and S6K2 are two of the most important downstream effectors of mTORC1.

Figure 2. Mechanisms connecting PTEN with metabolism

PTEN counteracts the activity of PI3K and, in this manner, decreases neoplastic transformation, decreases the negative feedback loop that inhibits insulin signaling, activates the BAT, and prevents the “Warburg effect”. This latter function is mediated in part by the PTEN mediated stimulation of the ubiquitin-ligase APC^CDH1. Metabolic protection is thought to be a consequence of a decreased negative feedback signaling and of increased energy expenditure (EE). The latter can be produced by increased BAT activity and by an increased oxidative phosphorylation, i.e. “anti-Warburg effect”. The combined effects of PTEN on cancer and metabolism can contribute to the increased longevity of Pten^tg.

Figure 3. Regulation of Ucp1 transcription

Ucp1 transcription in brown adipocytes is regulated by a “main switch” and by a “modulator”. The “main switch” is triggered by norepinephrine (NE) released by the sympathetic nervous system. NE, through ß3-adrenergic receptor (ß3AR) and PKA, activates CREB/CBP and elevates the levels of Ucp1 expression. PKA also activates fatty acid oxidation (FAO) in a transcriptional-independent manner. The “modulator” is positively regulated by PTEN or by pharmacological inhibitors of PI3K (PI3Ki), through deactivation of PI3K/AKT and ensuing activation of FOXO1/PGC1α, which positively regulates the transcription of Ucp1.