Cellular and molecular mechanisms in the hypoxic tissue: role of HIF‐1 and ROS

Zepeda, Andrea B.; Pessoa, Adalberto; Castillo, Rodrigo; Figueroa, Carolina A.; Pulgar, Víctor M.; Farías, Jorge G.

doi:10.1002/cbf.2985

Cited by 115 publications

(88 citation statements)

References 56 publications

(164 reference statements)

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“…Consequently, HIF-1a is constitutively repressed under normoxia. In contrast, increases in nitric oxide and reactive oxygen species are known to stabilize HIF-1a via PHD inhibition (Zepeda et al, 2013). In hypoxia, PHDs are inactivated, leading to HIF-1a stabilization and migration into the nucleus, where it can associate with HIF-1b and other transcriptional factors to facilitate its binding to HREs in the promoters of target genes.…”

Section: Hypoxia-inducible Factor 1a (Hif-1a)mentioning

confidence: 99%

Oxygen and viruses: a breathing story

Morinet

Parent

Bergeron

et al. 2015

Journal of General Virology

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The effect of oxygen on virus replication is complex, and the role of hypoxia-inducible factor 1a (HIF-1a) in the metabolism of virus-infected cells remains uncertain. Solid tumours are hypoxic, and some viruses use this low oxygen tension level to facilitate their replication in tumour cells, thereby causing cell lysis. In addition, the interactions between viruses and HIF-1a may stimulate a trained immunity. However, the evolutionary basis for the oxygen regulatory mechanism of virus replication is ill-defined and requires further investigation.

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Section: Hypoxia-inducible Factor 1a (Hif-1a)mentioning

confidence: 99%

Oxygen and viruses: a breathing story

Morinet

Parent

Bergeron

et al. 2015

Journal of General Virology

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“…Hypoxic adaptation is a typical example of a profound bioenergetics modulation (Brocato et al 2014;Denko 2008;Fukuda et al 2007;Greer et al 2012;Jiang et al 1996;Metallo et al 2011;Seagroves et al 2001;Semenza 2007Semenza , 2012aSemenza , b, 2013Taylor 2008;Zepeda et al 2013). It is often an inherent part of cancer development but occurs also under certain physiological conditions, such as in proliferating lymphocytes (Metallo et al 2011).…”

Section: Introductionmentioning

confidence: 98%

Aglycemia keeps mitochondrial oxidative phosphorylation under hypoxic conditions in HepG2 cells

Plecitá–Hlavatá

Ježek

2015

J Bioenerg Biomembr

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Cancer cell bioenergetics, maintaining mixed aerobic glycolysis (Warburg phenotype) and oxidative phosphorylation (OXPHOS), is not fully elucidated. Hypoxia-dependent OXPHOS suppression determines aerobic glycolysis. To elucidate further details, we studied hypoxic adaptation (up to 72 h at 5 % oxygen) of hepatocellular carcinoma HepG2 cells. The key regulatory component, hypoxia-inducible factor (HIF)-1α (HIF-1α) was stabilized at 5 h in 5 % oxygen for all three studied regimens, i.e. in glycolytic cells at 5 mM or 25 mM glucose, or in aglycemic (OXPHOS) cells when glucose was replaced by galactose. However, the conventional HIF-mediated suppression of respiration was prevented at aglycemia, which correlated with a high proportion of unphosphorylated pyruvate dehydrogenase (PDH) at 5 % oxygen. Such a modified HIF response in OXPHOS cells, termed as a non-canonical one, contrasted to conventional respiration suppression down to 45 % or 43 %, observed in hypoxia-adapted glycolytic cells at 5 mM or 25 mM glucose, respectively. These hypoxic glycolytic cells had normally highly phosphorylated PDH and most likely utilized pyruvate by aminotransferase reaction of glutaminolysis to feed at least suppressed respiration. Also, glycolytic cells were rather resistant towards the staurosporine-induced apoptosis, whereas aglycemic (OXPHOS) HepG2 cells exhibited much higher susceptibility. We conclude that aglycemia modulates the hypoxic HIF signaling toward a non-canonical response that is unable to carry out complete PDH phosphorylation, allowing a high pyruvate input for OXPHOS from the elevated glycolysis, which together with ongoing glutaminolysis maintain a virtually unchanged respiration. Similar OXPHOS revival may explain distinct tumor sensitivity to chemotherapy and other pharmacological interventions.

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“…Hypoxia-inducible factor 1 (HIF-1) is a transcriptional activator and is involved in a lot of pathophysiological processes under hypoxia (16). HIF-1 consists of an oxygen-sensitive α subunit (HIF-1α) and a constitutively expressed β subunit (HIF-1β) (17).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-inducible factor 1α participates in hypoxia-induced epithelial-mesenchymal transition via response gene to complement 32

Zhu

Zhao

2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to explore the function of response gene to complement 32 (RGC-32) in hypoxia-induced epithelial-mesenchymal transition (EMT) in pancreatic cancer. Three kinds of hypoxia-inducible factor 1α (HIF-1α) small interfering (si)RNA were synthesized and the different effects on the expression of HIF-1α were detected by western blotting. In human pancreatic cancer BxPC-3 cells, HIF-1α levels were diminished using siRNA transfection or HIF-1α inhibitor pretreatment, and the expression levels of RGC-32 and EMT-associated proteins were analyzed using reverse transcription-quantitative polymerase chain reaction and western blotting. Subsequently, the protein levels of epithelial marker, E-cadherin, and mesenchymal marker, vimentin, were determined by western blotting. Results demonstrated that HIF-1α-Homo-488 siRNA and HIF-1α-Homo-1216 siRNA diminished the protein level of HIF-1α. Compared with normoxia, hypoxia induced the levels of HIF-1α, RGC-32, N-cadherin and vimentin, but suppressed the expression of E-cadherin and cytokeratins. The inhibition of HIF-1α by HIF-1α-Homo-1216 siRNA transfection or HIF-1α inhibitor repressed hypoxia-induced HIF-1α, RGC-32, N-cadherin and vimentin, but increased the expression of E-cadherin and cytokeratins. When RGC-32 was knocked down, hypoxia-induced vimentin was suppressed; however, hypoxia-suppressed N-cadherin was released. In conclusion, the present results demonstrated that hypoxia induced the expression of HIF-1α to activate the levels of RGC-32, in turn to regulate the expression EMT-associated proteins for EMT. These findings revealed the function of RGC-32 in hypoxia-induced EMT and may have identified a novel link between HIF-1α and EMT for pancreatic cancer therapy. IntroductionPancreatic cancer is a highly lethal human gastrointestinal cancer (1). Although increasing methods are being applied for pancreatic cancer treatment, such as surgical resection and radiotherapy, the 5-year relative survival rate remains very dismal. A potential reason for the failure of the classical therapeutic approach may be explained by its high metastatic potential (2). Thus, it is critical to reveal the metastasis mechanism of pancreatic cancer. Epithelial-mesenchymal transition (EMT), the conversion from an epithelial to a mesenchymal phenotype, is a vital process for cancer invasion to surrounding tissues or metastasis to other organs (3). During the process of EMT, typical morphological changes occur, such as cell invasion and motility (4). The molecular indicators for EMT are the decrease of epithelial markers, such as E-cadherin, and the increase in the levels of mesenchymal markers, such as N-cadherin and vimentin (5). Significant efforts are required to investigate the mechanism of EMT for cancer control and the improvement of cure rate.Response gene to complement 32 (RGC-32), first identified in 1998, is induced by complement and involved in cell cycle activation (6). RGC-32 is comprehensively expressed in the placenta, skeletal muscle, kidney, ...

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Cellular and molecular mechanisms in the hypoxic tissue: role of HIF‐1 and ROS

Cited by 115 publications

References 56 publications

Oxygen and viruses: a breathing story

Oxygen and viruses: a breathing story

Aglycemia keeps mitochondrial oxidative phosphorylation under hypoxic conditions in HepG2 cells

Hypoxia-inducible factor 1α participates in hypoxia-induced epithelial-mesenchymal transition via response gene to complement 32

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