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HIF-1: hypoxia-inducible factor or dysoxia-inducible factor?

Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain

¹Correspondence: Department of Pharmacology, Faculty of Pharmacy, Seville, C/Professor Garcia Gonzalez, 41011, Sevilla, Spain. E-mail: mlopezlazaro{at}us.es

	ABSTRACT

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes involved in diverse aspects of cellular and integrative physiology, including energy metabolism, cell growth, survival, invasion, migration or angiogenesis. The activity of this transcription factor is known to be increased by hypoxia, but also by a growing number of apparently unrelated factors that can activate it even in nonhypoxic conditions. Here I propose a model in which an alteration in oxygen metabolism is the key cellular event involved in HIF-1 activation under hypoxic and nonhypoxic conditions. This new perspective unifies previously unrelated observations and predicts cellular processes and therapeutic strategies that may modify HIF-1 activity. This may have relevance, for instance, to cancer, as HIF-1 overexpression is observed in many human cancers and has been associated with increased patient mortality. López-Lázaro, M. HIF-1: hypoxia-inducible factor or dysoxia-inducible factor?

Key Words: oxygen • ATP • glycolysis • hydrogen peroxide • cancer

	INTRODUCTION

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
HIF-1 IS A HETERODIMERIC transcription factor that consists of a constitutively expressed HIF-1ß subunit and a HIF-1 subunit, the expression of which is highly regulated. The activity of this transcription factor mainly depends on the levels of HIF-1, which, as for any protein, is determined by the rates of protein synthesis and protein degradation. It is considered that HIF-1 synthesis is regulated by activation of the phosphatidylinositol 3-kinase (PI3K) and ERK mitogen-activated protein kinase (MAPK) pathways, while its degradation is regulated by O₂-dependent prolyl hydroxylation (1 , 2) . Despite its name, it is known that HIF is not only stabilized by hypoxia, but also by a growing number of apparently unrelated factors, which can activate HIF-1 in nonhypoxic conditions. Thus, it has been reported that HIF-1 can be activated, for instance, by superoxide anion, hydrogen peroxide, TNF-, glucose (Glc) metabolites, prostaglandin E₂, the ligands of tyrosine kinase receptors epidermal growth factor (EGF), IGF1, and platelet-derived growth factor (PDGF), p53 loss of function, Ras, cyclooxygenase-2 activity, the poison arsenic, or the green tea constituent epigallocatechin-3-gallate (1 , 3 4 5 6 7 8 9 10 11) . At present, the main mechanism underlying HIF-1 activation under hypoxic and nonhypoxic conditions is poorly understood.

HIF-1 is activated in physiological conditions but also in various pathological conditions such as cancer. Interest in the role of HIF-1 in cancer biology has grown exponentially in the last two decades, as this factor activates the transcription of many genes that code for proteins that are involved in angiogenesis, Glc metabolism, cell proliferation/survival and invasion/metastasis (1) . In fact, it seems that all oncogenes and tumor-suppressor gene pathways are connected with the HIF-1 pathway (12) . Besides, HIF-1 overexpression has been observed in many human cancers and has been associated with increased patient mortality in several cancer types (1) . Reducing the levels of HIF-1 therefore seems an appealing anticancer strategy. This might be achieved by developing HIF-1 inhibitors (1) , but also by identifying a/the key cellular event responsible for HIF-1 activation and developing strategies to modulate it. The present communication proposes that the key cellular event involved in HIF-1 activation is an alteration in oxygen metabolism. The relevance of this hypothesis is discussed.

	KEY ROLE OF ALTERED OXYGEN METABOLISM IN HIF-1 REGULATION

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
Figure 1 represents a new model in which an altered oxygen metabolism is the key cellular event involved in HIF-1 regulation. This model shows that oxygen (O₂) can be reduced to H₂O via oxidative phosphorylation (oxphos) or via reactive oxygen species (ROS) generation (O₂^·–, H₂O₂). I propose that the main mechanism involved in HIF-1 activation is a decrease in O₂ metabolism via oxphos and/or an increase in O₂ metabolism via ROS generation.

View larger version (16K): [in this window] [in a new window]   Figure 1. Key role of altered oxygen metabolism in HIF-1 regulation

	Glycolysis activates HIF-1

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
Lu et al. have provided evidence that the end products of glycolytic metabolism can promote HIF-1 protein stability and activate HIF-1-inducible gene expression. They showed that these effects were independent of hypoxia and H₂O₂ generation and that pyruvate was the key glycolytic metabolite promoting HIF-1 accumulation (8) . The same research group showed that the Glc metabolite, and tricarboxylic acid (TCA) cycle product, oxaloacetate could also activate HIF-1 (13) . They have recently proposed that the activity of pyruvate and oxaloacetate on HIF-1 is mediated by a reversible inactivation of HIF-1 prolyl hydroxylases (HPH); this inactivation prevents HPH-dependent HIF-1 degradation therefore increasing HIF-1 protein levels (14) . The Glc and TCA cycle metabolites succinate and fumarate have also been reported to activate HIF-1 by directly competing for the 2-oxoglutarate site of HPH (15) ; 2-oxoglutarate is required by HPH-dependent HIF-1 degradation. In brief, there is evidence that glycolysis activation can increase HIF-1 activity via accumulation of Glc metabolites.

	Anything that activates glycolysis can potentially increase HIF-1

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
Since Glc metabolites can activate HIF-1, anything that activates glycolysis can potentially increase HIF-1. Glycolysis can be activated by a decrease in the cellular ATP levels and intracellular alkalinization (16 , 17) . A decrease in ATP levels can be caused by structural defects in oxidative phosphorylation, intracellular alkalinization or hypoxia.

A decrease in ATP levels can potentially activate HIF-1
It is well known that ATP levels control glycolysis via allosteric inhibition of the enzyme phosphofructokinase (PFK), the most important control site of glycolysis. Thus, when ATP decreases, PFK activity increases and glycolysis is activated to compensate such ATP deficit (16 , 17) . Since activation of glycolysis can increase HIF-1 activity (8) , a decrease in ATP levels can potentially activate HIF-1. Accordingly, it has been reported that AMP-activated protein kinase (AMPK), a protein that functions as an energy sensor to provide metabolic adaptations under ATP-deprived conditions, activates HIF-1 (18) .

Structural defects in oxphos can potentially activate HIF-1
As shown in Fig. 2 , ATP generation through oxhphos requires undamaged oxphos structures. Therefore, defects in the protein ATP synthase would probably decrease ATP generation through oxphos; this might increase the glycolytic rate resulting in HIF-1 activation. This supposition is supported by experimental evidence showing that most cancer cells have decreased expression of ATP synthase (19 , 20) and increased HIF-1 levels (1) .

View larger version (100K): [in this window] [in a new window]   Figure 2. Oxidative phosphorylation (oxphos). In the process of oxphos, high-energy electrons from NADH (and FADH2) are passed along the electron-transport chain, located in the inner mitochondrial membrane, to O2. This electron transport drives three enzyme complexes that pump H+ from the mitochondrial matrix to the intermembrane space. This generates an electrochemical H+ gradient across the inner mitochondrial membrane, which is used by ATP synthase to phosphorylate ADP to form ATP (16) . VDAC: voltage-dependent anion channel.

Intracellular alkalinization can potentially activate HIF-1
It is known that intracellular alkalinization and decreased ATP levels activate glycolysis (16 , 17 , 21) . Thus, it has been demonstrated that the activity of PFK is extremely sensitive to small changes in pH in the physiological range, a high pH increasing the activity of this enzyme (21) . In addition, a decrease in the cytosolic concentrations of H⁺ (intracellular alkalinization) decreases the electrochemical H⁺ gradient across the inner mitochondrial membrane therefore decreasing ATP synthesis through oxphos (see Fig. 2 ); such ATP decrease would activate PFK and glycolysis (16) . Therefore, since it is well accepted that intracellular alkalinization can increase PFK activity and activate glycolysis (17 , 21) , and given that glycolysis can activate HIF-1 (8) , intracellular alkalinization can potentially increase HIF-1 (see Fig. 3 ).

View larger version (12K): [in this window] [in a new window]   Figure 3. Possible activation of HIF-1 by intracellular alkalinization (see text).

A recent paper seems to disagree with this prediction, as it shows that acidic pH activates HIF-1 (22) . It is important to note that intracellular pH values were not measured and that the HIF-1 activation observed was caused by extracellular acidification and not by intracellular acidification (22) . Besides, extracellular acidification is usually produced as a consequence of intracellular alkalinization. For instance, because the Na⁺/H⁺ exchanger NHE1 and the H⁺/lactate cotransporter are activated in cancer, cancer cells have increased H⁺ transport from the inside to the outside; this produces extracellular acidification and intracellular alkalinization (23) . Indeed, it has been reported that tumor cells have alkaline intracellular pH values (7.12–7.65 compared with 6.99–7.20 in normal (N) tissues) and acidic interstitial extracellular pH values (6.2–6.9 compared with 7.3–7.4) (23) . The experimental observations that cancer cells have both intracellular alkalinization (23 24 25 26) and increased HIF-1 levels (1) support the hypothesis that intracellular alkalinization may result in HIF-1 activation. There is further evidence that supports this prediction. For instance, it has been shown that intracellular alkalinization enhances O₂^·– generation (27) , and O₂^·– can increase HIF-1 (3 , 4) . In addition, the ligands of tyrosine kinase receptors EGF, IGF1, and PDGF are known to both induce intracellular alkalinization (28 , 29) and increase HIF-1 (5) . Prostaglandin E₂ also induces intracellular alkalinization and increases HIF-1 (1) . HIF-1 is also activated by cyclooxygenase-2 activity (6) , which is increased by intracellular alkalinization (30) . Besides, it has been suggested that intracellular alkalinization may be the molecular mechanism responsible for the destabilization and loss of function of the tumor suppressor protein p53 (31) , and p53 loss of function has been shown to induce HIF-1 (1) . In brief, intracellular alkalinization is known to increase glycolysis and glycolysis can activate HIF-1 (Fig. 3) . Furthermore, situations that produce intracellular alkalinization also activate HIF-1. This suggests that intracellular alkalinization can potentially activate HIF-1.

	H2O2 activates HIF-1

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
Several reports suggest that mitochondria-derived ROS are required for the N induction of HIF-1 during hypoxia, and that this effect is mediated by H₂O₂ (3 , 32 33 34) . Exogenous H₂O₂ has also been observed to stabilize HIF-1, and catalase overexpression prevented HIF-1 activity (3 , 32) . The PI3K and MAPK pathways may mediate H₂O₂-induced HIF-1 stabilization, as H₂O₂ activates these pathways (35 , 36) and these pathways are known to stabilize HIF-1 (1) . On the other hand, H₂O₂-induced HIF-1 stabilization may also be mediated by a decrease in Fe²⁺. H₂O₂ is an oxidant able to oxidize Fe²⁺ to Fe³⁺, for instance, via the Fenton reaction. Conversion of Fe²⁺ into Fe³⁺ would reduce Fe²⁺, which is required by HPH to hydroxylate HIF-1 and target this transcription factor for ubiquitylation and proteosomal degradation (1 , 2) . Accordingly, it was demonstrated recently that the cellular accumulation of H₂O₂ decreases the availability of Fe²⁺ and prevents HIF-1 degradation (37) .

	Anything that increases the cellular levels of H2O2 can potentially increase HIF-1

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
The model shown in Fig. 1 predicts that any situation that increases O₂ metabolism via ROS generation can increase the cellular levels of H₂O₂ and increase HIF-1 activity. There are many examples that support this assumption. For instance, hypoxia can stabilize HIF-1 via ROS generation (3 , 32 33 34) . TNF- (4) and Ras (10) also increased HIF-1 activity under nonhypoxic conditions via ROS generation, and ROS scavenging reduced HIF-1 activity (4 , 10) . Drugs able to generate ROS may also induce HIF-1. For instance, arsenic and the flavonoid from green tea, epigallocatechin-3-gallate, are known to generate ROS (38 , 39) and to induce HIF-1 activation (7 , 9) .

	Hypoxia can regulate HIF-1 via H2O2 increase and via glycolysis activation

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
Although it has been shown that mitochondria-derived H₂O₂ is required for the N induction of HIF-1 during hypoxia (3 , 32 33 34) , other reports have shown that hypoxia-induced HIF-activation does not require H₂O₂ (40) . Figure 1 shows that, besides activating HIF-1 via H₂O₂, hypoxia may also activate HIF-1 via decrease in O₂ metabolism through oxphos and subsequent ATP decrease and glycolysis activation. Accordingly, it is well known that hypoxia increases glycolysis (Pasteur effect) and that glycolysis can activate HIF-1 (8) . Indeed, it has been reported that hypoxia-induced glycolysis (Pasteur effect) is mediated by HIF-1 activation and that ATP levels are dramatically reduced during hypoxia in the absence of HIF-1 (41) .

	WHY IS HIF-1 INCREASED IN CANCER?

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 
HIF-1 overexpression is observed in many human cancers and has been associated with increased patient mortality. At present, it is considered that cancers have increased HIF-1 because of intratumoral hypoxia and genetic alterations in the pathways responsible for HIF-1 synthesis and HIF-1 degradation (1) . According to the present hypothesis, I propose that HIF-1 is enhanced in cancer because cancer cells have a reduced O₂ metabolism via oxphos and an increased O₂ metabolism via ROS generation. These two situations can activate HIF-1 (Fig. 1) and are frequently observed in cancer.

There are several lines of evidence that suggest that cancer cells have a reduced O₂ metabolism via oxphos. Firstly, unaltered oxphos structures are required for metabolizing O₂ via oxphos, and altered oxphos structures are commonly observed in cancer cells (19 , 20) . Second, O₂ metabolism through oxphos requires an electrochemical H⁺ gradient along the inner mitochondrial membrane. Intracellular alkalinization decreases such gradient and is a normal feature of cancer cells (23 24 25 26) . Third, it is evident that O₂ metabolism via oxphos requires O₂, and it is well accepted that some areas in malignant tumors have reduced O₂ levels. Finally, the high rates of glycolysis found in cancer cells (42) suggest that these cells have a reduced O₂ metabolism via oxphos and depend on glycolysis for keeping adequate ATP levels. Accordingly, it has recently been reported that inhibition of glycolysis severely depletes ATP in cancer cells (43) . It seems that cancer cells may have reduced O₂ metabolism via oxphos, which may be caused by damaged oxphos structures, intracellular alkalinization, or hypoxia. This would result in reduced ATP generation through oxphos, increased glycolysis and HIF-1 activation.

Extensive literature suggests that cancer cells have increased O₂ metabolism via ROS (44 45 46 47) . It has been shown that tumor cells generate O₂^·– and H₂O₂ constitutively and in large amounts (46 , 47) . Since cancer cells seem to have increased levels of H₂O₂ and HIF-1, and since H₂O₂ is known to stabilize HIF-1 (3 , 32 33 34) , it seems possible that HIF-1 may be increased in cancer cells because these cells have increased generation of H₂O₂.

In conclusion, the present communication proposes an integrating model in which an alteration in O₂ metabolism plays a central role in HIF-1 activation under hypoxic and nonhypoxic conditions. This model predicts that any situation that decreases O₂ metabolism via oxphos and/or increases O₂ metabolism via ROS generation can potentially activate HIF-1. This hypothesis can be used to explain why HIF-1 is increased in cancer, as cancer cells seem to have a reduced O₂ metabolism via oxphos and an increased O₂ metabolism via ROS generation. Understanding why cancers have this alteration in O₂ metabolism might be exploited to develop anticancer strategies. I propose that preventing/reducing intracellular alkalinization (e.g., by decreasing the activity of the Na⁺/H⁺ exchanger) and ROS generation (e.g., by limiting the exposure to substances that produce ROS in their metabolism or by scavenging ROS) might decrease HIF-1 activity and produce anticancer effects.

Received for publication October 6, 2005. Accepted for publication December 6, 2005.

	REFERENCES

TOP ABSTRACT INTRODUCTION KEY ROLE OF ALTERED... Glycolysis activates HIF-1 Anything that activates... H2O2 activates HIF-1 Anything that increases the... Hypoxia can regulate HIF-1... WHY IS HIF-1 INCREASED... REFERENCES

 

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