• BMB Reports
• /
• v.56 no.11
• /
• pp.584-593
• /
• 2023

Hypoxia, a widespread occurrence observed in various malignant tumors, results from rapid tumor growth that outpaces the oxygen supply. Tumor hypoxia precipitates several effects on tumor biology; these include activating angiogenesis, intensifying invasiveness, enhancing the survival of tumor cells, suppressing anti-tumor immunity, and fostering resistance to therapy. Aligned with the findings that correlate CMGC kinases with the regulation of Hypoxia-Inducible Factor (HIF), a pivotal modulator, reports also indicate that hypoxia governs the activity of CMGC kinases, including DYRK1 kinases. Prolyl hydroxylation of DYRK1 kinases by PHD1 constitutes a novel mechanism of kinase maturation and activation. This modification "primes" DYRK1 kinases for subsequent tyrosine autophosphorylation, a vital step in their activation cascade. This mechanism adds a layer of intricacy to comprehending the regulation of CMGC kinases, and underscores the complex interplay between distinct post-translational modifications in harmonizing precise kinase activity. Overall, hypoxia assumes a substantial role in cancer progression, influencing diverse aspects of tumor biology that include angiogenesis, invasiveness, cell survival, and resistance to treatment. CMGC kinases are deeply entwined in its regulation. To fathom the molecular mechanisms underpinning hypoxia's impact on cancer cells, comprehending how hypoxia and prolyl hydroxylation govern the activity of CMGC kinases, including DYRK1 kinases, becomes imperative. This insight may pave the way for pioneering therapeutic approaches that target the hypoxic tumor microenvironment and its associated challenges.

• Biomolecules & Therapeutics
• /
• v.18 no.2
• /
• pp.145-151
• /
• 2010

Oxygen supply into inside solid tumor is often diminished, which is called hypoxia. Many gene transcriptions were activated by hypoxia-inducible factor (HIF)-$1{\alpha}$. Here, we investigated the effect of hypoxia on paclitaxel-resistance induction in HeLa cervical tumor cells. When HeLa cells were incubated under hypoxia condition, HIF-$1{\alpha}$ level was increased. In contrast, paclitaxel-mediated tumor cell death was reduced by the incubation under hypoxia condition. Paclitaxel-mediated tumor cell death was also inhibited by treatment with DMOG, chemical HIF-$1{\alpha}$ stabilizer, in a dose-dependent manner. A significant increase in intracellular ROS level was detected by the incubation under hypoxia condition. A basal level of cell density was increased in response to 10 nM $H_2O_2$. HIF-$1{\alpha}$ level was increased by treatment with various concentration of $H_2O_2$. The increased level of HIF-$1{\alpha}$ by hypoxia was reduced by the treatment with N-acetylcysteine (NAC), a well-known ROS scavenger. Paclitaxel-mediated tumor cell death was increased by treatment with NAC. Taken together, these findings demonstrate that hypoxia could play a role in paclitaxel-resistance induction through ROS-mediated HIF-$1{\alpha}$ stabilization. These results suggest that hypoxia-induced ROS could, in part, control tumor cell death through an increase in HIF-$1{\alpha}$ level.

• The Korean Journal of Physiology and Pharmacology
• /
• v.3 no.1
• /
• pp.93-100
• /
• 1999

The present study was designed to assess the roles of $PLA_2$ activation and arachidonic acid (AA) metabolites in hypoxia-induced renal cell injury. Hypoxia increased LDH release in a dose-dependent manner in rabbit renal cortical slices, and this increase was significant after 20-min hypoxia. The hypoxia-induced LDH release was prevented by amino acids, glycine and alanine, and extracellular acidosis (pH 6.0). Buffering intracellular $Ca^{2+}$ by a chelator, but not omission of $Ca^{2+}$ in the medium produced a significant reduction in hypoxia-induced LDH release. The effect of hypoxia was blocked by $PLA_2$ inhibitors, mepacrine, butacaine, and dibucaine. A similar effect was observed by a 85-kD $cPLA_2$ inhibitor $AACOCF_3.$ AA increased hypoxia-induced LDH release, and albumin, a fatty acid absorbent, prevented the LDH release, suggesting that free fatty acids are involved in hypoxia-induced cell injury. These results suggest that $PLA_2$ activation and its metabolic products play important roles in pathogenesis of hypoxia-induced cell injury in rabbit renal cortical slices.

• Bulletin of the Korean Chemical Society
• /
• v.30 no.4
• /
• pp.897-901
• /
• 2009

Heme oxygenase-1 (HO-1) is an anti-inflammatory and anti-apoptotic protein and has been applied to various gene therapy researches. However, constitutive expression of HO-1 may induce deleterious side effects. In this research, hypoxia inducible HO-1 expression plasmid, pEpo-SV-HO-1, was constructed with the erythropoietin (epo) enhancer and simian virus 40 (SV40) promoter to avoid these unwanted side effects. Dexamethasone conjugated polyethylenimine (PEI-Dexa) was used as a gene carrier. It was previously reported that dexamethasone protected cardiomyocytes from apoptosis under hypoxia. In this research, PEI-Dexa reduced the caspase-3 level in hypoxic H9C2 cardiomyocytes as a derivative of dexamethasone, suggesting that PEI-Dexa is an anti-apoptotic reagent as well as a gene carrier. pEpo-SV-HO-1 was transfected to H9C2 cardiomyocytes using PEI-Dexa and the cells were incubated under normoxia or hypoxia. HO-1 expression was induced in the pEpo-SV-HO-1 transfected cells under hypoxia. In addition, cell viability under hypoxia was higher in the pEpo-SV-HO-1 transfected cells than the pEpo-SV-Luc transfected cells. Also, caspase-3 level was reduced in the pEpo-SV-HO-1 transfected cells under hypoxia. In addition to the anti-apoptotic effect of PEI-Dexa, hypoxia inducible HO-1 expression by pEpo-SVHO- 1 may be helpful to protect cardiomyocytes under hypoxia. Therefore, pEpo-SV-HO-1/PEI-Dexa complex may be useful for ischemic heart disease gene therapy.

• Molecules and Cells
• /
• v.44 no.10
• /
• pp.710-722
• /
• 2021

Hypoxia, or low oxygen tension, is a hallmark of the tumor microenvironment. The hypoxia-inducible factor-1α (HIF-1α) subunit plays a critical role in the adaptive cellular response of hypoxic tumor cells to low oxygen tension by activating gene-expression programs that control cancer cell metabolism, angiogenesis, and therapy resistance. Phosphorylation is involved in the stabilization and regulation of HIF-1α transcriptional activity. HIF-1α is activated by several factors, including the mitogen-activated protein kinase (MAPK) superfamily. MAPK phosphatase 3 (MKP-3) is a cytoplasmic dual-specificity phosphatase specific for extracellular signal-regulated kinase 1/2 (Erk1/2). Recent evidence indicates that hypoxia increases the endogenous levels of both MKP-3 mRNA and protein. However, its role in the response of cells to hypoxia is poorly understood. Herein, we demonstrated that small-interfering RNA (siRNA)-mediated knockdown of MKP-3 enhanced HIF-1α (not HIF-2α) levels. Conversely, MKP-3 overexpression suppressed HIF-1α (not HIF-2α) levels, as well as the expression levels of hypoxia-responsive genes (LDHA, CA9, GLUT-1, and VEGF), in hypoxic colon cancer cells. These findings indicated that MKP-3, induced by HIF-1α in hypoxia, negatively regulates HIF-1α protein levels and hypoxia-responsive genes. However, we also found that long-term hypoxia (>12 h) induced proteasomal degradation of MKP-3 in a lactic acid-dependent manner. Taken together, MKP-3 expression is modulated by the hypoxic conditions prevailing in colon cancer, and plays a role in cellular adaptation to tumor hypoxia and tumor progression. Thus, MKP-3 may serve as a potential therapeutic target for colon cancer treatment.

• Ocean and Polar Research
• /
• v.44 no.1
• /
• pp.1-11
• /
• 2022

Hypoxia can affect water-atmosphere methane flux by controlling the production and consumption processes of methane in coastal areas. Seasonal methane concentration and fluxes were quantified to evaluate the effects of seasonal hypoxia in Dangdong Bay (Gyeongsangnamdo, Jinhae Bay, South Korea). Sediment-water methane flux increased more than 300 times during hypoxia (normoxia and hypoxia each 6, 1900 µmol m^-2 d^-1), and water-atmospheric methane flux and bottom methane concentration increased about 2, 10 times (normoxia and hypoxia each 190, 420 µmol m^-2 d^-1; normoxia and hypoxia each 22, 230 nM). Shoaling of anaerobic decomposition of organic matter in the sediments during the hypoxia (August) was confirmed by the change of the depth at which the maximum hydrogen sulfide concentration was detected. Shoaling shortens the distance between the water column and methanogenesis section to facilitate the inflow of organic matter, which can lead to an increase in methane production. In addition, since the transport distance of the generated methane to the water column is shortened, consumption of methane will be reduced. The combination of increased production and reduced consumption could increase sediment-aqueous methane flux and dissolved methane, which is thought to result in an increase in water-atmospheric methane flux. We could not observe the emission of methane accumulated during the hypoxia due to stratification, so it is possible that the estimated methane flux to the atmosphere was underestimated. In this study, the increase in methane flux in the coastal area due to hypoxia was confirmed, and the necessity of future methane production studies according to oxygen conditions in various coastal areas was demonstratedshown in the future.

• Biomolecules & Therapeutics
• /
• v.5 no.1
• /
• pp.1-7
• /
• 1997

This study was done to investigate the effect of vitamin C on hypoxia/reoxygenation-induced hepatic injury ul isolated perfused rat liver. Isolated livers from rats fasted 18 hours were subjected to 45 min of hypoxia followed by reoxygenation for 45 min. The perfusion medium used was Krebs-Henseleit bicarbonate buffer (pH 7.4) and 0.5 mmol/L of vitamin C was added to the perfusate. Alanine aminotransferase (ALI) and lactate dehydrogenase (LDH) levels were significantly increased by hypoxia/reoxygenation. These increases were augmented by vitamin C. Glucose output and bile flow were markedly decreased by hypoxia/reoxygenation. Vitamin C aggavated the decrease of glucose output but had little effect on bile flow. Our findings suggest that hypoxia/reoxygenation diminishes hepatic metabolic and secretory functions, and vitamin C significantly aggravates these changes.

• The Journal of Korean Medicine
• /
• v.25 no.2
• /
• pp.67-76
• /
• 2004

Objectives : This study was designed to investigate the protective mechanisms of Palmul-tang on hypoxia-induced cytotoxicity in H9c2 cardiomyoblast cells. Methods : In this study, we used H9c2 cells. Cells were subjected to hypoxia in the absence and presence of $1000\mu\textrm{g}/ml$ Palmul-tang for 24 hrs. Cells were treated with various concentrations of Palmul-tang for 24 hrs. Cell viability was measured by MTT assay. Hypoxia markedly decreased the viability of H9c2 cells, which was characterized with apparent apoptotic features such as chromatin condensation as well as fragmentation of genomic DNA and nuclei. Results : Palmul-tang significantly reduced hypoxia-induced cell death and apoptotic characteristics. Also, Palmul-tang prevented mitochondrial dysfunction including the disruption of mitochondrial membrane permeability transition (MPT) and an increase in expression of apoptogenic Bcl-2 proteins in hypoxia-H9c2 cells. Conclusions; This study suggests that the protective effects of Palmul-tang against hypoxic damages may be mediated by the modulation of Bcl-2, Bax expression.

• The Korean Journal of Nuclear Medicine
• /
• v.39 no.2
• /
• pp.141-145
• /
• 2005

Hypoxia (decreased tissue oxygen tension) is a component of many diseases such as tumors, cerebrovascular diseases and ischemic heart diseases. Although hypoxia can be secondary to a low inspired $pO_2$ or a variety of lung disorders, the most common cause is ischemia due to an oxygen demand greater than the local oxygen supply. In the heart tissue, hypoxia is often observed in persistent low-flow states, such as hibernating myocardium. Direct "hot spot" imaging of myocardial tissue hypoxia is potentially of great clinical importance because it may provide a means of identifying dysfunctional chronically ischemic but viable hibernating myocardium. A series of radiopharmaceuticals that incorporate nitroimidazole moieties have been synthesized to detect decreased local tissue pO2. In contrast to agents that localize in proportion to perfusion, these agents concentrate in hypoxic tissue. However, the ideal agents are not developed yet and the progress is very slow. Furthermore, the research focus is on tumor hypoxia nowadays. This review introduces the myocardial hypoxia imaging with summarizing the development of radiopharmaceuticals.

• Journal of Pharmaceutical Investigation
• /
• v.37 no.5
• /
• pp.287-290
• /
• 2007

Intrinsic or acquired resistance to chemotherapeutic drugs is one of the major obstacles to effective cancer treatment. Hypoxia is widespread in solid tumors as a consequence of decreased blood flow in the tumor-derived neovasculature. The recent finding of a link between hypoxia and chemoresistance prompted us to investigate whether hypoxia induces doxorubicin resistance in human MCF-7 breast cancer cells. Low oxygen concentration decreased the doxorubicin sensitivity in MCF-7 cells. The expression of p-glycoprotein, a major MDR-related transporter, and those of apoptosis-related proteins (anti-apoptotic Bcl-2, Bcl-XL and pro-apoptotic Bax) were not altered by hypoxia in MCF-7 cells. Intracellular uptake of doxorubicin was significantly decreased under hypoxic conditions. Decreased cellular uptake of doxorubicin under hypoxia may contribute to causing doxorubicin resistance in these cells. The use of agents that can modulate the doxorubicin uptake for adjuvant therapy may contribute to improving the therapeutic efficacy of doxorubicin in breast cancer patients.