Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State

Garcı́a-Cao, Isabel; Song, Min Sup; Hobbs, Robin M.; Laurent, Gaëlle; Giorgi, Carlotta; Boer, Vincent C.J. de; Anastasiou, Dimitrios; Ito, Keisuke; Sasaki, Atsuo T.; Rameh, Lucia E.; Carracedo, Arkaitz; Heiden, Matthew G. Vander; Cantley, Lewis C.; Pinton, Paolo; Haigis, Marcia C.; Pandolfi, Pier Paolo

doi:10.1016/j.cell.2012.02.030

Cited by 348 publications

(330 citation statements)

References 79 publications

Supporting

Mentioning

300

Contrasting

Unclassified

Order By: Relevance

“…In PTENsilenced cells, a reduction in the kinetics of Ca 2 þ release from the ER that significantly blunted also the cytosolic and the mitochondrial Ca 2 þ responses, accounts for reduced sensitivity to apoptosis. However, in agreement with previous studies, 35 global PTEN overexpression did not increase the mitochondrial Ca 2 þ response after agonist stimulation. We argued that PTEN's regulation of Ca 2 þ homeostasis relied specifically on its localization to ER and MAMs.…”

Section: Discussionsupporting

confidence: 93%

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

et al. 2013

View full text Add to dashboard Cite

The tumor suppressor activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is thought to be largely attributable to its lipid phosphatase activity. PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to directly antagonize the phosphoinositide 3-kinase-Akt pathway and prevent the activating phosphorylation of Akt. PTEN has also other proposed mechanisms of action, including a poorly characterized protein phosphatase activity, protein-protein interactions, as well as emerging functions in different compartment of the cells such as nucleus and mitochondria. We show here that a fraction of PTEN protein localizes to the endoplasmic reticulum (ER) and mitochondriaassociated membranes (MAMs), signaling domains involved in calcium ( 2 þ ) transfer from the ER to mitochondria and apoptosis induction. We demonstrate that PTEN silencing impairs ER Ca 2 þ release, lowers cytosolic and mitochondrial Ca 2 þ transients and decreases cellular sensitivity to Ca 2 þ -mediated apoptotic stimulation. Specific targeting of PTEN to the ER is sufficient to enhance ER-to-mitochondria Ca 2 þ transfer and sensitivity to apoptosis. PTEN localization at the ER is further increased during Ca 2 þ -dependent apoptosis induction. Importantly, PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and this correlates with the reduction in their phosphorylation and increased Ca 2 þ release. We propose that ER-localized PTEN regulates Ca 2 þ release from the ER in a protein phosphatase-dependent manner that counteracts Akt-mediated reduction in Ca 2 þ release via IP3Rs. These findings provide new insights into the mechanisms and the extent of PTEN tumor-suppressive functions, highlighting new potential strategies for therapeutic intervention.

show abstract

Section: Discussionsupporting

confidence: 93%

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Herein, we show that the oncosuppressor PTEN plays a dominant role in the membrane expression of GLUT1 and glucose uptake in thyroid cancer cells. It has been shown that the ectopic hyper-expression of PTEN contrasts the uptake and the large glycolytic consumption of glucose observed in proliferating cancer cells (Garcia-Cao et al 2012). Consistently, we found that the transgenic reintroduction of PTEN in FTC133 abrogates the membrane expression of GLUT1.…”

Section: Discussionsupporting

confidence: 74%

PTEN regulates plasma membrane expression of glucose transporter 1 and glucose uptake in thyroid cancer cells

Morani

Phadngam

Follo

et al. 2014

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

Glucose represents an important source of energy for the cells. Proliferating cancer cells consume elevated quantity of glucose, which is converted into lactate regardless of the presence of oxygen. This phenomenon, known as the Warburg effect, has been proven to be useful for imaging metabolically active tumours in cancer patients by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glucose is internalised in the cells by glucose transporters (GLUTs) belonging to the GLUT family. GLUT1 (SLC2A1) is the most prevalent isoform in more aggressive and less differentiated thyroid cancer histotypes. In a previous work, we found that loss of expression of PTEN was associated with increased expression of GLUT1 on the plasma membrane (PM) and probability of detecting thyroid incidentalomas by FDG-PET. Herein, we investigated the molecular pathways that govern the expression of GLUT1 on the PM and the glucose uptake in WRO (expressing WT PTEN) and FTC133 (PTEN null) follicular thyroid cancer cells cultured under glucose-depleted conditions. The membrane expression of GLUT1 was enhanced in glucose-deprived cells. Through genetic manipulations of PTEN expression, we could demonstrate that the lack of this oncosuppressor has a dominant effect on the membrane expression of GLUT1 and glucose uptake. We conclude that loss of function of PTEN increases the probability of cancer detection by FDG-PET or other glucose-based imaging diagnosis.

show abstract

“…Taken together, our results suggest that PRL2 activates Akt by downregulating PTEN. In support of our finding that PRL2 functions as a negative regulator of PTEN, "Super-PTEN" transgenic mouse lines with higher PTEN expression also show reduced body size due to decreased cell proliferation (35). Recent studies reveal that even a subtle reduction of PTEN expression can substantially increase tumor formation in mice (36).…”

Section: Discussionsupporting

confidence: 68%

Phosphatase of Regenerating Liver 2 (PRL2) Is Essential for Placental Development by Down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and Activating Akt Protein

Dong

Zhang

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:The physiological functions of the PRL phosphatases are poorly understood. Results: PRL2 deficiency causes placental insufficiency, decreased spongiotrophoblast proliferation, and growth retardation. Conclusion: PRL2 plays an important role in placental development by down-regulating PTEN and activating Akt. Significance: This study provides the first evidence of an essential function for PRL2 and offers a biochemical basis for PRLs as oncoproteins to repress PTEN expression.

show abstract

Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State

Cited by 348 publications

References 79 publications

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

PTEN regulates plasma membrane expression of glucose transporter 1 and glucose uptake in thyroid cancer cells

Phosphatase of Regenerating Liver 2 (PRL2) Is Essential for Placental Development by Down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and Activating Akt Protein

Contact Info

Product

Resources

About