Hypoxia and HIF-1α protect A549 cells from drug-induced apoptosis

Schnitzer, Steffen E.; Schmid, Tobias; Zhou, Jie; Brüne, Bernhard

doi:10.1038/sj.cdd.4401864

Cited by 47 publications

(40 citation statements)

References 11 publications

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“…Cells showed an abrogated caspase-3 activation and chromatin condensation, two hallmarks of apoptosis, in response to etoposide treatment (5). Stimulation of A549 cells with 150 Amol/L etoposide for 4 h under serum-free conditions provoked massive cell death followed by caspase-3 activity measurements (specific activity of caspase-3: normoxia, 2.1 F 1.5 nmol/mg/min; normoxia + etoposide, 68.4 F 18.0 nmol/mg/min).…”

Section: Resultsmentioning

confidence: 99%

“…Caspase-3 activity was quantified following the cleavage of Ac-DEVD-AMC as described previously (5). Briefly, cells were resuspended in assay buffer (100 mmol/L HEPES, 0.1% CHAPS, 10% sucrose, 1 mmol/L DTT), sonicated on ice (15 s), and centrifuged at 15,000 Â g for 15 min.…”

Section: Caspase-3 Activity Assaymentioning

confidence: 99%

“…To circumvent periods of insufficient nutrient and oxygen supply, cells evolve mechanisms to adapt to such conditions, with the notion that hypoxia-inducible factor-1 (HIF-1) appears of particular importance. HIF-1 regulates the expression of >70 target genes, including proapoptotic ones (4), but also provokes an antiapoptotic phenotype of tumor cells (5)(6)(7)(8). In addition, there are HIF-1-independent pathways that promote cell survival under hypoxia by activating, for example, phosphoinositide 3-kinase (PI3K) or extracellular signalregulated kinase 1/2 [p42/44 mitogen-activated protein kinase (MAPK; ref.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells

Schnitzer

Weigert

Zhou

et al. 2009

Molecular Cancer Research

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Hypoxia and signaling via hypoxia-inducible factor-1 (HIF-1) is a key feature of solid tumors and is related to tumor progression as well as treatment failure. Although it is generally accepted that HIF-1 provokes tumor cell survival and induces chemoresistance under hypoxia, HIF-1-independent mechanisms operate as well. We present evidence that conditioned medium obtained from A549 cells, incubated for 24 h under hypoxia, protected naive A549 cells from etoposide-induced cell death. Lipid extracts generated from hypoxiaconditioned medium still rescued cells from apoptosis induced by etoposide. Specifically, the bioactive lipid sphingosine-1-phosphate (S1P) not only was essential for cell viability of A549 cells but also protected cells from apoptosis. We noticed an increase in sphingosine kinase 2 (SphK2) protein level and enzymatic activity under hypoxia, which correlated with the release of S1P into the medium. Knockdown of SphK2 using specific small interfering RNA relieved chemoresistance of A549 cells under hypoxia and conditioned medium obtained from SphK2 knockdown cells was only partially protective. Coincubations of conditioned medium with VPC23019, a S1P 1 /S1P 3 antagonist, reduced protection of conditioned medium, with the further notion that p42/ 44 mitogen-activated protein kinase transmits autocrine or paracrine survival signaling downstream of S1P 1 /S1P 3 receptors. Our data suggest that hypoxia activates SphK2 to promote the synthesis and release of S1P, which in turn binds to S1P 1 /S1P 3 receptors, thus activating p42/44 mitogen-activated protein kinase to convey autocrine or paracrine protection of A549 cells.

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Section: Resultsmentioning

confidence: 99%

Section: Caspase-3 Activity Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells

Schnitzer

Weigert

Zhou

et al. 2009

Molecular Cancer Research

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“…171 HIF-1a overexpression can induce chemotherapeutic drug resistance. 172 Suppression of HIF-1a can also influence the sensitivity to angiostatin, a naturally occurring inhibitor of angiogenesis. 173 This may occur in part by suppressing glucose transporter-1 and vascular endothelial growth factor expression, 173 although other investigators have observed that suppression of HIF-1a will also affect the expression of Bcl-2 family members such as Bid.…”

Section: Mtorc1-hif Drug Resistancementioning

confidence: 99%

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

et al. 2011

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“…Therefore, inadequate pharmacokinetics in these areas may reduce the effectiveness of anticancer drugs even though they are effective under hypoxic conditions or even inhibit HIF-1α. Furthermore, HIF-1 knockdown cells can normally grow and survive in hypoxic conditions 7,33 . HIF-1 independent mechanisms of drug resistance in hypoxia are under-investigation, but are still rarely reported.…”

Section: Introduction -Hypoxia-induced Chemoresistancementioning

confidence: 99%

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

Doktorova

Hraběta

Khalil

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. Results. Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results. Conclusions. The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development.

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Hypoxia and HIF-1α protect A549 cells from drug-induced apoptosis

Cited by 47 publications

References 11 publications

Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells

Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

Hypoxia-induced chemoresistance in cancer cells: The role of not only HIF-1

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