Hypoxia-Inducible Factor-1α and the Glycolytic Phenotype in Tumors

Robey, Ian; Lien, Anthony D; Welsh, Sarah J.; Baggett, Brenda; Gillies, Robert J.

doi:10.1593/neo.04430

Cited by 228 publications

(173 citation statements)

References 37 publications

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“…We demonstrated that latent KSHV infection of endothelial cells induces aerobic glycolysis and decreases oxidative phosphorylation, the properties that define the Warburg effect, a common effect in over 90% of cancers (10). Additionally we show that KSHV induction of the Warburg effect is not universal but specifically occurs in endothelial cells, the relevant KS tumor-cell type.…”

Section: Discussionmentioning

confidence: 66%

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Delgado

Carroll

Punjabi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

203

233

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Kaposi's sarcoma (KS) is the most commonly reported tumor in parts of Africa and is the most common tumor of AIDS patients worldwide. KS-associated herpesvirus (KSHV) is the etiologic agent of KS. Although KS tumors contain many cell types, the predominant cell is the spindle cell, a cell of endothelial origin that maintains KSHV latency. KSHV activates many cell-signaling pathways but little is known about how KSHV alters cellular metabolism during latency. The Warburg effect, a common metabolic alteration of most tumor cells, is defined by an increase in aerobic glycolysis and a decrease in oxidative phosphorylation as an energy source. The Warburg effect adapts cells to tumor environments and is necessary for the survival of tumor cells. During latent infection of endothelial cells, KSHV induces aerobic glycolysis and lactic acid production while decreasing oxygen consumption, thereby inducing the Warburg effect. Inhibitors of glycolysis selectively induce apoptosis in KSHV-infected endothelial cells but not their uninfected counterparts. Therefore, similar to cancer cells, the Warburg effect is necessary for maintaining KSHV latently infected cells. We propose that KSHV induction of the Warburg effect adapts infected cells to tumor microenvironments, aiding the seeding of KS tumors. Additionally, inhibitors of glycolysis may provide a unique treatment strategy for latent KSHV infection and ultimately KS tumors.human herpesvirus-8 | gamma-herpesvirus | latency | glycolysis

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Section: Discussionmentioning

confidence: 66%

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Delgado

Carroll

Punjabi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

203

233

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“…RNA concentrations were assessed spectrophotometrically (UV-visible spectrophotometer, Cary 50 Scan, Varian) at 260nm. 400ng of total RNA was reverse transcribed (Superscript TM II, Invitrogen) and analyzed by Reverse Transcriptase-PCR (RT-PCR) (Hotstar Taq DNA polymerase; Qiagen, Hilden, Germany) using genespecific primers (Table 1) for collagen 1 (Col1α1), collagen II (Col2α1), aggrecan and transcription factor Sox9 , hypoxia inducible factor-1 (HIF) 1α isoform (Gao et al, 2005), metalloproteinase-2 (MMP2) (Shan et al, 2005), glycosylphosphatidylinositol-anchored cell surface protein CD24 (Fujita et al, 2005), glucose transporter (GLUT-1) (Robey et al, 2005), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a housekeeping gene (Sanchez et al, 2005). The PCR fragments were resolved on a 1.5% agarose gel and stained with ethidium bromide.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Cell-seeded polyurethane-fibrin structures – A possible system for intervertebral disc regeneration

Mauth

Bono²,

Haas³

et al. 2009

eCM

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Nowadays, intervertebral disc (IVD) degeneration is one of the principal causes of low back pain involving high expense within the health care system. The long-term goal is the development of a medical treatment modality focused on a more biological regeneration of the inner nucleus pulposus (NP). Hence, interest in the endoscopic implantation of an injectable material took center stage in the recent past. We report on the development of a novel polyurethane (PU) scaffold as a mechanically stable carrier system for the reimplantation of expanded autologous IVDderived cells (disc cells) to stimulate regenerative processes and restore the chondrocyte-like tissue within the NP. Primary human disc cells were seeded into newly developed PU spheroids which were subsequently encapsulated in fibrin hydrogel. The study aims to analyze adhesion properties, proliferation capacity and phenotypic characterization of these cells. Polymerase chain reaction was carried out to detect the expression of genes specifically expressed by native IVD cells. Biochemical analyses showed an increased DNA content, and a progressive enhancement of total collagen and glycosaminoglycans (GAG) was observed during cell culture. The results suggest the synthesis of an appropriate extracellular matrix as well as a stable mRNA expression of chondrogenic and/or NP specific markers. In conclusion, the data presented indicate an alternative medical approach to current treatment options of degenerated IVD tissue.

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“…These include processes leading to enhanced oxygen delivery (angiogenesis), increased glycolytic metabolism and a switch from oxidative phosphorylation to anaerobic glycolysis (Gatenby and Gillies, 2004). The increased glycolytic activity under hypoxic conditions requires increased glucose uptake via glucose transporter proteins and increased expression of enzymes required for glycolysis (Akakura et al, 2001;Robey et al, 2005). These responses usually occur via changes in gene expression mediated by Hif-1a (Semenza, 2000;Semenza et al, 2000;Mahon et al, 2001).…”

Section: N H H-gd A204 A673mentioning

confidence: 99%

Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

et al. 2006

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Hypoxia inducible factor-1 (HIF-1) is the major transcription factor and key regulator of adoptive responses to hypoxia. Although it usually promotes tumor cell survival under hypoxia, it has also been implied to trigger apoptosis. Although the impact of hypoxia has been extensively studied in many adult solid tumors, its role in most childhood tumors, for example, in rhabdomyosarcoma (RMS) or Ewing sarcoma (ES), has not yet been addressed. Here, we report that hypoxia protects A204 RMS and A673 ES cells against anticancer drug-or tumor necrosis factor-related apoptosis-inducing ligandinduced apoptosis and that Hif-1a plays a key role in conferring apoptosis resistance under hypoxia. Although a functional HIF-1 pathway and proapoptotic proteins such as p53 and Bcl-2/E1B 19 kDa interacting protein 3 were activated under hypoxia in both A204 RMS and A673 ES cells, these cells remained refractory to apoptosis. Concomitant analysis of antiapoptotic proteins revealed that hypoxia induced expression of Bcl-2 and inhibitor of apoptosis proteins (IAP)-2 as well as proteins associated with anaerobic metabolism such as the glucose transporter protein GLUT-1 and the glycolytic enzyme Aldolase A. Specific downregulation of Hif-1a by RNA interference significantly enhanced apoptosis under hypoxia by preventing the hypoxia-mediated increase in GLUT-1 expression without altering expression levels of the antiapoptotic proteins Bcl-2 or cIAP-2. Moreover, glucose deprivation-induced apoptosis of A204 RMS and A673 ES cells was inhibited under hypoxic conditions in a Hif-1a-dependent manner. As GLUT-1 was induced via Hif-1a under hypoxia in A204 RMS and A673 ES, these findings suggest that the Hif-1a-mediated increase in glucose uptake plays an important role in conferring apoptosis resistance. Thus, hypoxia-inducible genes may represent novel targets for therapeutic intervention in some pediatric tumors, which warrants further investigation.

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Hypoxia-Inducible Factor-1α and the Glycolytic Phenotype in Tumors

Cited by 228 publications

References 37 publications

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Induction of the Warburg effect by Kaposi's sarcoma herpesvirus is required for the maintenance of latently infected endothelial cells

Cell-seeded polyurethane-fibrin structures – A possible system for intervertebral disc regeneration

Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance

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