Over-expression of hypoxia-inducible factor-1? increases the invasive potency of LNCaP cells in vitro

Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.

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Inhibitor of DNA Binding 1 Is Induced during Kidney Ischemia-Reperfusion and Is Critical for the Induction of Hypoxia-Inducible Factor-1α

BioMed Research International ◽

10.1155/2016/4634386 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Dan Wen ◽

Yan-Fang Zou ◽

Yao-Hui Gao ◽

Qian Zhao ◽

Yin-Yin Xie ◽

...

Keyword(s):

Dna Binding ◽

Ischemia Reperfusion ◽

Hypoxia Inducible Factor ◽

Kidney Injury ◽

Mrna Levels ◽

Hypoxia Inducible Factor 1 ◽

Renal Tubular ◽

Inhibitor Of Dna Binding

In this study, rat models of acute kidney injury (AKI) induced by renal ischemia-reperfusion (I/R) and HK-2 cell models of hypoxia-reoxygenation (H/R) were established to investigate the expression of inhibitor of DNA binding 1 (ID1) in AKI, and the regulation relationship between ID1 and hypoxia-inducible factor 1 alpha (HIF-1α). Through western blot, quantitative real-time PCR, immunohistochemistry, and other experiment methods, the induction of ID1 after renal I/R in vivo was observed, which was expressed mainly in renal tubular epithelial cells (TECs). ID1 expression was upregulated in in vitro H/R models at both the protein and mRNA levels. Via RNAi, it was found that ID1 induction was inhibited with silencing of HIF-1α. Moreover, the suppression of ID1 mRNA expression could lead to decreased expression and transcription of HIF-1αduring hypoxia and reoxygenation. In addition, it was demonstrated that both ID1 and HIF-1αcan regulate the transcription of twist. This study demonstrated that ID1 is induced in renal TECs during I/R and can regulate the transcription and expression of HIF-1α.

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In vitro cobalt-stimulated hypoxia-inducible factor-1 overexpression does not correlate with cancer risk from cobalt exposure in humans

Toxicology Research and Application ◽

10.1177/2397847319850167 ◽

2019 ◽

Vol 3 ◽

pp. 239784731985016

Author(s):

Carr J Smith ◽

Thomas A Perfetti

Keyword(s):

Cancer Risk ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Cobalt Exposure

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HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

Journal of Experimental Medicine ◽

10.1084/jem.20050177 ◽

2005 ◽

Vol 202 (11) ◽

pp. 1493-1505 ◽

Cited By ~ 227

Author(s):

Holger K. Eltzschig ◽

Parween Abdulla ◽

Edgar Hoffman ◽

Kathryn E. Hamilton ◽

Dionne Daniels ◽

...

Keyword(s):

Transcriptional Repression ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Nucleoside Transporter ◽

In Vivo Models ◽

Equilibrative Nucleoside Transporter ◽

Hypoxia Inducible Factor 1 ◽

And Function

Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)–dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1α mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.

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Emodin Decreases Hepatic Hypoxia-Inducible Factor-1α by Inhibiting its Biosynthesis

The American Journal of Chinese Medicine ◽

10.1142/s0192415x16500555 ◽

2016 ◽

Vol 44 (05) ◽

pp. 997-1008 ◽

Cited By ~ 4

Author(s):

Feifei Ma ◽

Lijuan Hu ◽

Ming Yu ◽

Feng Wang

Keyword(s):

Hepg2 Cells ◽

Mammalian Cells ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Hepatic Cells ◽

Diet Induced Obesity ◽

Pathological Conditions ◽

Therapeutic Value ◽

Normal Stability

Hypoxia-inducible factor-1 (HIF-1) is an [Formula: see text] dimeric transcription factor. Because HIF-1[Formula: see text] is instable with oxygen, HIF-1 is scarce in normal mammalian cells. However, HIF-1[Formula: see text] is expressed in pathological conditions such as cancer and obesity. Inhibiting HIF-1[Formula: see text] may be of therapeutic value for these pathologies. Here, we investigated whether emodin, derived from the herb of Rheum palmatum L, which is also known as Chinese rhubarb, and is native to China, regulates HIF-1[Formula: see text] expression. Male C57BL/6 mice without or with diet-induced obesity were treated with emodin for two weeks, while control mice were treated with vehicle. HIF-1[Formula: see text] expression was determined by Western blot. We found that emodin inhibited obesity-induced HIF-1[Formula: see text] expression in liver and skeletal muscle but did not regulate HIF-1[Formula: see text] expression in the kidneys or in intra-abdominal fat. In vitro, emodin inhibited HIF-1[Formula: see text] expression in human HepG2 hepatic cells and Y1 adrenocortical cells. Further, we investigated the mechanisms of HIF-1[Formula: see text] expression in emodin-treated HepG2 cells. First, we found that HIF-1[Formula: see text] had normal stability in the presence of emodin. Thus, emodin did not decrease HIF-1[Formula: see text] by stimulating its degradation. Importantly, emodin decreased the activity of the signaling pathways that led to HIF-1[Formula: see text] biosynthesis. Interestingly, emodin increased HIF-1[Formula: see text] mRNA in HepG2 cells. This may be a result of feedback in response to the emodin-induced decrease in the protein of HIF-1[Formula: see text]. In conclusion, emodin decreases hepatic HIF-1[Formula: see text] by inhibiting its biosynthesis.

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Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance

Molecular and Cellular Biology ◽

10.1128/mcb.24.7.2875-2889.2004 ◽

2004 ◽

Vol 24 (7) ◽

pp. 2875-2889 ◽

Cited By ~ 242

Author(s):

Janine T. Erler ◽

Christopher J. Cawthorne ◽

Kaye J. Williams ◽

Marianne Koritzinsky ◽

Bradley G. Wouters ◽

...

Keyword(s):

Drug Resistance ◽

Solid Tumors ◽

Hypoxia Inducible Factor ◽

Oxygen Deprivation ◽

Translation Efficiency ◽

Down Regulation ◽

Drug Induced ◽

Human Colon Cancer ◽

Hypoxia Inducible Factor 1

ABSTRACT Solid tumors with disorganized, insufficient blood supply contain hypoxic cells that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle to curative treatment of solid tumors, can occur via suppression of apoptosis, a process controlled by pro- and antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was dispensable for the down-regulation of Bad but required for that of Bid, consistent with the binding of HIF-1α to a hypoxia-responsive element (positions −8484 to −8475) in the bid promoter. Oxygen deprivation resulted in proteosome-independent decreased expression of Bax in vitro, consistent with a reduction in global translation efficiency. The physiological relevance of Bid and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation resulted in decreased drug-induced apoptosis and clonogenic resistance to agents with different mechanisms of action. The contribution of Bid and/or Bax down-regulation to drug responsiveness was demonstrated by the relative resistance of normoxic cells that had no or reduced expression of Bid and/or Bax and by the finding that forced expression of Bid in hypoxic cells resulted in increased sensitivity to the topoisomerase II inhibitor etoposide.

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