Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

Tennant, Daniel A.; Frezza, Christian; MacKenzie, Elaine D.; Nguyen, Quang Dé; Zheng, Liang; Selak, Mary; Roberts, D. F.; Dive, Caroline; Watson, D. G.; Aboagye, Eric O.; Gottlieb, Eyal

doi:10.1038/onc.2009.250

Cited by 105 publications

(114 citation statements)

References 46 publications

(55 reference statements)

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“…5C), we treated PIK3CA WT and MUT cells with a membrane-permeable 2OG-ester derivative, dimethyl-(dm)-2OG (28,29) and assessed effects on cell proliferation. We confirmed an increase in intracellular 2OG levels, and also decreased levels of aspartate (Fig.…”

Section: Pik3ca Mutant Cell Lines Display An Enhanced Requirement Formentioning

confidence: 99%

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Ilić

Birsoy

Aguirre

et al. 2017

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

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Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale lossof-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.

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Section: Pik3ca Mutant Cell Lines Display An Enhanced Requirement Formentioning

confidence: 99%

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Ilić

Birsoy

Aguirre

et al. 2017

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

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“…However, other markers and methods can be used to analyze the hypoxia pathway. For example, the involvement of the prolyl hydroxylase (PHD) enzyme, which induce hydroxylation of proline residues under normoxia, as well as the von Hippel-Lindau (VHL) protein, which recognize hydroxylated prolines and induce the poly-ubiquitination to mediate proteasomal HIF degradation, need to be analyzed for a full overview of the pathway 29,30 . Moreover, ubiquitous detection of HIFs would also determine the protein stability and degradation that can be alter 31,32 .…”

Section: Representative Resultsmentioning

confidence: 99%

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

Bözec

Hannemann

2016

JoVE

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Considering that adipose tissue (AT) is an endocrine organ, it can influence whole body metabolism. Excessive energy storage leads to the dysregulation of adipocytes, which in turn induces abnormal secretion of adipokines, triggering metabolic syndromes such as obesity, dyslipidemia, hyperglycemia, hyperinsulinemia, insulin resistance and type 2 diabetes. Therefore, investigating the molecular mechanisms behind adipocyte dysregulation could help to develop novel therapeutic strategies. Our protocol describes methods for evaluating the molecular mechanism affected by hypoxic conditions of the AT, which correlates with adipocyte apoptosis in adult mice. This protocol describes how to analyze AT in vivo through gene expression profiling as well as histological analysis of adipocyte differentiation, proliferation and apoptosis during hypoxia exposure, ascertained through staining of hypoxic cells or HIF-1α protein. Furthermore, in vitro analysis of adipocyte differentiation and its responses to various stimuli completes the characterization of the molecular pathways behind possible adipocyte dysfunction leading to metabolic syndromes.

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“…Under normoxic conditions, HIF-1α is vulnerable to degradation. This degradation process is blocked under hypoxic conditions, resulting in the accumulation of HIF-1α (24). Under hypoxic conditions, HIF-1α is capable of regulating anaerobic metabolism by inducing the expression of its target gene, and promoting angiogenesis and an increase of erythropoietin, which ensures that the hypoxic tissues and cells maintain at a certain oxygen concentration and tolerate the hypoxic environment (25,26).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective mechanism of HIF-1α overexpression in the early stage of acute cerebral infarction in rats

Sun

Geng

2016

Experimental and Therapeutic Medicine

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Abstract. The present study aimed to explore the expression and neuroprotective mechanism of hypoxia inducible factor (HIF-1α) in the brain tissue of a rat model of early acute cerebral infarction. A total of 64 Sprague Dawley rats were randomly divided into surgery and sham groups and the model of focal cerebral infarction was established by the suture-occluded method. In the sham group, blood vessels were separated but not occluded. Rats in the surgery and sham groups were subdivided into eight groups (n=4/group). Blood samples was collected at 8 time points including 30 min and 1, 3, 6, 12, 48, 24 and 72 h, respectively, and HIF-1α content was detected using ELISA. Brain tissues of rats in all groups were harvested following blood collection. HIF-1α protein expression was detected by immunohistochemistry and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling was used to analyze the brain cell apoptosis index. ELISA results demonstrated that rats in the surgery group began to express HIF-1α within 30 min, and HIF-1α expression levels gradually increased, peaking at 12 h. HIF-1α expression levels were significantly increased in the surgery group at all time points, as compared with the sham group (P<0.05). The concentration of HIF-1α decreased rapidly in 12 h. At various time points, HIF-1α protein expression in the brain tissue of rats in the sham group was negative. HIF-1α protein expression was significantly increased in the surgery group (P<0.05), peaking at 12 h, and decreasing after this point. As compared with the sham group, the apoptosis indices of the brain tissue of rats in the surgery group exhibited a gradual increasing trend with significant decreases observed after 12 h (P<0.05). Intra-group comparison of all indices in the surgery group, indicated that there was a statistically significant difference between postoperative 12 h and other time points (P<0.05).In conclusion, the present study demonstrated that HIF-1α was highly expressed in the brain tissue of rat models of early acute cerebral infarction. The results also indicated that HIF-1α significantly reduced the apoptosis of infarcted cells, suggesting that HIF-1α may have a neuroprotective role in early acute cerebral infarction.

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Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

Cited by 105 publications

References 46 publications

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

Neuroprotective mechanism of HIF-1α overexpression in the early stage of acute cerebral infarction in rats

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