PTEN in cancer, metabolism, and aging

doi:10.1016/j.tem.2012.11.002

Trends in Endocrinology & Metabolism

Volume 24, Issue 4, April 2013, Pages 184-189

https://doi.org/10.1016/j.tem.2012.11.002 Get rights and content

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.

Section snippets

PTEN and cancer protection

PTEN is a well-established tumor-suppressor gene, being one of the most frequently mutated genes in human tumors and with germline mutations causing cancer-predisposition syndromes 1, 2, 3. The protein is expressed in all tissues in the body and contains a tensin-like domain and a phosphatase catalytic domain [4]. During tumor development, PTEN mutations and deletions often occur that inactivate or decrease PTEN function [3]. Genetic inactivation of PTEN is frequently found in glioblastomas,

PTEN and obesity

Overexpression of PTEN in mice results in reduced body weight 12, 13. This phenotype is not surprising considering that PTEN antagonizes a main anabolic pathway, such as the insulin-activated PI3K/AKT pathway. Strikingly, however, PTEN overexpression results in mice that are hyperphagic, which, combined with their reduced body weight, suggests a poorer capacity to store the energy of nutrients and thus lower metabolic efficiency. Indeed, calorimetric measurements demonstrated an increased

PTEN and longevity

Given the aforementioned phenotypes associated with increased Pten dosage, namely protection from cancer and obesity, PTEN might also have an effect on longevity. Indeed, Pten^tg mice exhibit higher median and maximal lifespans, a phenomenon observed both in males and females [12]. The effect of PTEN on longevity is, however, independent of its action as a tumor suppressor, because when longevity is measured only in those mice that do not develop cancer (longevity of cancer-free mice), Pten

Insulin signaling versus long-term insulin sensitivity

The fact that many mouse models with reduced insulin signaling, including Pten^tg mice, have increased lifespan, begs the question of why these mice do not develop life-limiting pathologies associated with insulin resistance. This conundrum can be explained by the existence of negative feedback loops within the IIS pathway, which are most relevant under conditions of chronic nutrient overload, or during aging. In particular, negative feedback loops emanate from FOXO and S6K that inhibit the

The ‘anti-Warburg effect’ of PTEN

Cancer cells, in addition to deregulated control of cell proliferation and survival, must also reprogram their metabolism to fuel cell growth and division [29]. The most remarkable metabolic change of cancer cells is the so-called ‘Warburg effect’, by which cells catabolize large amounts of glucose through glycolysis. This massive increase in glycolytic flux maintains the necessary ATP levels and, at the same time, promotes the generation of anabolic intermediates [30]. The direct connection

Specific effects of PTEN on brown adipose tissue (BAT)

In the context of studying glucose uptake in vivo, it was found that the BAT of Pten^tg mice was abnormally active compared to wt mice (Figure 2) [12]. Brown adipocytes constitute the main cell type of the BAT and are also found in clusters interspersed within the white adipose tissue (WAT) 40, 41. The main function of brown adipocytes is to burn nutrients either in response to cold (cold-induced thermogenesis) or in response to nutritional excess (diet-induced thermogenesis) 40, 41. Uncoupling

Concluding remarks

The new metabolic roles of PTEN, as a negative regulator of glycolysis and a positive regulator of energy expenditure, are part of a general trend of discoveries by which oncogenes and tumor suppressors are found to be intimately connected to metabolism. This should not be surprising, given the fact that cell growth and proliferation are tightly dependent on metabolism. A major pending question for the immediate future is to dissect the extent to which the metabolic effects of tumor suppressors

Acknowledgments

Work in the laboratory of M.S. is funded by the Spanish National Cancer Research Centre (CNIO) and by grants from the Spanish Ministry of Economy (SAF), the European Commission (European Research Council Advanced Grant), the Regional Government of Madrid, the Botin Foundation, the Ramon Areces Foundation, and the AXA Foundation.

References (51)

L. Simpson et al.
PTEN: life as a tumor suppressor
Exp. Cell Res.
(2001)
T. Maehama et al.
The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate
J. Biol. Chem.
(1998)
B.D. Manning et al.
AKT/PKB signaling: navigating downstream
Cell
(2007)
N. Hay
Interplay between FOXO, TOR, and Akt
Biochim. Biophys. Acta
(2011)
A. Ortega-Molina
Pten positively regulates brown adipose function, energy expenditure, and longevity
Cell Metab.
(2012)
I. Garcia-Cao
Systemic elevation of PTEN induces a tumor-suppressive metabolic state
Cell
(2012)
P. Polak
Adipose-specific knockout of raptor results in lean mice with enhanced mitochondrial respiration
Cell Metab.
(2008)
C. Blouet
Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis
Cell Metab.
(2008)
W.H. Chung
The role of genetic variants in human longevity
Ageing Res. Rev.
(2010)
D. Hanahan et al.
Hallmarks of cancer: the next generation
Cell
(2011)

Cited by (165)

miRNAs as potential game-changers in bone diseases: Future medicinal and clinical uses
2023, Pathology Research and Practice
MicroRNAs (miRNAs), short, highly conserved non-coding RNA, influence gene expression by sequential mechanisms such as mRNA breakdown or translational repression. Many biological processes depend on these regulating substances, thus changes in their expression have an impact on the maintenance of cellular homeostasis and result in the emergence of a variety of diseases. Relevant studies have shown in recent years that miRNAs are involved in many stages of bone development and growth. Additionally, abnormal production of miRNA in bone tissues has been closely associated with the development of numerous bone disorders, such as osteonecrosis, bone cancer, and bone metastases. Many pathological processes, including bone loss, metastasis, the proliferation of osteosarcoma cells, and differentiation of osteoblasts and osteoclasts, are under the control of miRNAs. By bringing together the most up-to-date information on the clinical relevance of miRNAs in such diseases, this study hopes to further the study of the biological features of miRNAs in bone disorders and explore their potential as a therapeutic target.
Alpha-ketoglutarate as a potent regulator for lifespan and healthspan: Evidences and perspectives
2023, Experimental Gerontology
Aging is a natural process that determined by a functional decline in cells and tissues as organisms are growing old, resulting in an increase at risk of disease and death. To this end, many efforts have been made to control aging and increase lifespan and healthspan. These efforts have led to the discovery of several anti-aging drugs and compounds such as rapamycin and metformin. Recently, alpha-ketoglutarate (AKG) has been introduced as a potential anti-aging metabolite that can control several functions in organisms, thereby increases longevity and improves healthspan. Unlike other synthetic anti-aging drugs, AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, and synthesized in the body. It plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors. AKG exerts its effects through different mechanisms such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation. Herein, we summarize the recent findings of AKG-related lifespan and healthspan studies and discuss AKG associated cell and molecular mechanisms involved in increasing longevity, improving reproduction, and modulating stem cells and cancer cells behavior. We also discuss the promises and limitations of AKG for delaying aging and other potential applications.
Expression profile of genes related to pregnancy maintenance in Dromedary Camel during the first trimester
2023, Animal Reproduction Science
So far, few signals involved in embryo-maternal dialogue have been identified in pregnant she-camel. Our objective was to investigate expression profiles of genes relevant to uterine extracellular matrix remodeling (ITGB4, SLCO2A1, FOS, and JUN), uterine tissue vascularization, and placental formation (VEGFA, PGF, and PDGFA), embryonic growth and development (IGF1 and PTEN), plus cell death of uterine tissue (BCL2) in early pregnant versus non-pregnant she-camels. Forty genital tracts (20 pregnant and 20 non-pregnant) and blood samples were collected from abattoirs. Total RNA was extracted from uterine tissues and qRT-PCR was conducted for candidate genes. Serum concentrations of progesterone (P4) and estradiol17-β (E2) were measured. Expression of ITGB4, FOS, and PGF genes increased (P < 0.001) in the right uterine horn of pregnant versus non-pregnant she-camels. Moreover, JUN, SLCO2A1, VEGFA, and PTEN mRNAs were up-regulated (P < 0.001) in various segments of uterine tissues in pregnant groups. The PDGFA transcript was over-expressed (P < 0.001) in both uterine horns of pregnant groups. Additionally, IGF1 was higher (P < 0.001) in the right horn and the uterine body of pregnant groups, and expression of BCL2 was increased (P < 0.001) in the pregnant uterine body. Moreover, serum concentrations of P4 were higher (P < 0.001) and E2 lower (P < 0.05) in pregnant she-camels. Taken together, the fine-tuning of genes related to implantation, matrix formation, vascularization, and placental formation is highly required for successful pregnancy in she-camels.
Quercetin 3-O-glucuronide-rich lotus leaf extract promotes a Brown-fat-phenotype in C<inf>3</inf>H<inf>10</inf>T<inf>1/2</inf> mesenchymal stem cells
2023, Food Research International
Lotus (Nelumbo nucifera Gaertn.) is an aquatic perennial crop planted worldwide and its leaf (also called “He-Ye”) has therapeutic effects on obesity. However, whether the underlying mechanism leads to increased energy expenditure by activation of brown adipocytes has not been clarified. Here, murine C₃H₁₀T_1/2 mesenchymal stem cells (MSCs) were employed to investigate the effects of ethanol extracts from lotus leaf (LLE) on brown adipocytes formation and the underlying molecular mechanisms. The results showed LLE was rich in polyphenols (383.7 mg/g) and flavonoids (178.3 mg/g), with quercetin 3-O-glucuronide (Q3G) the most abundant (128.2 μg/mg). In LLE-treated C₃H₁₀T_1/2 MSCs, the expressions of lipolytic factors (e.g., ATGL, HSL, and ABHD5) and brown regulators (e.g., Sirt1, PGC-1α, Cidea, and UCP1) were significantly upregulated compared to that in the untreated MSCs. Furthermore, LLE promoted mitochondrial biogenesis and fatty acid β-oxidation, as evidenced by increases in the expression of Tfam, Cox7A, CoxIV, Cox2, Pparα, and Adrb3. Likewise, enhanced browning and mitochondrial biogenesis were also observed in Q3G-stimulated cells. Importantly, LLE and Q3G induced phosphorylation of AMPK accompanied by a remarkable increase in the brown fat marker UCP1, while pretreatment with Compound C (an AMPK inhibitor) reversed these changes. Moreover, stimulating LLE or Q3G-treated cells with CL316243 (a beta3-AR agonist) increased p-AMPKα/AMPKα ratio and UCP1 protein expression, indicating β3-AR/AMPK signaling may involve in this process. Collectively, these observations suggested that LLE, especially the component Q3G, stimulates thermogenesis by activating brown adipocytes, which may involve the β3-AR/AMPK signaling pathway.
Restoring the anti-tumor property of PTEN: A promising oral cancer treatment
2022, Oral Oncology
Recapitulation of anti-aging phenotypes by global overexpression of PTEN in mice
2024, GeroScience

View all citing articles on Scopus

View full text

Trends in Endocrinology & Metabolism

ReviewArticle Series: Cancer and MetabolismPTEN in cancer, metabolism, and aging

Section snippets

PTEN and cancer protection

PTEN and obesity

PTEN and longevity

Insulin signaling versus long-term insulin sensitivity

The ‘anti-Warburg effect’ of PTEN

Specific effects of PTEN on brown adipose tissue (BAT)

Concluding remarks

Acknowledgments

Exp. Cell Res.

J. Biol. Chem.

Cell

Biochim. Biophys. Acta

Cell Metab.

Cell

Cell Metab.

Cell Metab.

Ageing Res. Rev.

Cell

Cell Metab.

Cell

Cell

Cell Metab.

Cell Metab.

Ageing Res. Rev.

New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway

Proc. Natl. Acad. Sci. U.S.A.

PTEN loss in the continuum of common cancers, rare syndromes and mouse models

Nat. Rev. Cancer

The functions and regulation of the PTEN tumour suppressor

Nat. Rev. Mol. Cell Biol.

Subtle variations in Pten dose determine cancer susceptibility

Nat. Genet.

PTEN and the PI3-kinase pathway in cancer

Annu. Rev. Pathol.

mTOR: from growth signal integration to cancer, diabetes and ageing

Nat. Rev. Mol. Cell Biol.

Forkhead box O as a sensor, mediator, and regulator of redox signaling

Antioxid. Redox Signal.

PTEN mutations as a cause of constitutive insulin sensitivity and obesity

N. Engl. J. Med.

Metabolic control by S6 kinases depends on dietary lipids

PLoS ONE

Review
Article Series: Cancer and Metabolism
PTEN in cancer, metabolism, and aging