HIF-1α Confers Aggressive Malignant Traits on Human Tumor Cells Independent of Its Canonical Transcriptional Function

Yoo, Young Gun; Christensen, Jared; Huang, L. Eric

doi:10.1158/0008-5472.can-10-2360

Cited by 49 publications

(55 citation statements)

References 51 publications

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“…The c-Myc downregulation in doxorubicin-resistant MG-63 cells together with MDR-1/P-gp overexpression suggest an inverse correlation between the two proteins in human osteosarcoma, as already described for N-Myc and MDR-1 in neuroblastoma (35) and for c-Myc and MDR-1 in rhabdomyosarcoma (36). Importantly, HIF-1α has recently been found to repress the activity of various molecules, including c-Myc, by an innovative HRE-independent mechanism that does not require DNA binding activity (37,38). Moreover, Hayashi et al (39) demonstrated a non-canonical mechanism of action of HIF-1α that counteracts c-Myc effects on gene expression.…”

Section: Discussionsupporting

confidence: 55%

Involvement of HIF-1α activation in the doxorubicin resistance of human osteosarcoma cells

2014

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Abstract. Osteosarcoma is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, survival outcomes remain unsatisfactory, particularly in patients with metastatic and/or recurrent disease. Unfortunately, treatment failure is commonly due to the development of chemoresistance, for which the underlying molecular mechanisms remain unclear. The aim of the present study was to investigate the role of hypoxia-inducible factor 1α (HIF-1α) and its signalling pathways as mediators of drug-resistance in human osteosarcoma. Toward this aim, we established two osteosarcoma cell lines selected for resistance to doxorubicin, a drug of choice in the treatment of this tumour. Our results showed that the multidrug resistance (MDR) phenotype was also mediated by HIF-1α, the most important regulator of cell adaptation to hypoxia. Our data showed that this transcription factor promoted the outward transport of intracellular doxorubicin by activating the P-glycoprotein (P-gp) expression in osteosarcoma cells maintained in normoxic conditions. In addition, it hindered doxorubicin-induced apoptosis by regulating the expression of c-Myc and p21. Finally, we observed that the doxorubicinresistant cells maintained for 2 months of continuous culture in a drug-free medium, lost their drug-resistance and this effect was associated with the absence of HIF-1α expression. The emerging role of HIF-1α in osteosarcoma biology indicates its use as a valuable therapeutic target.

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Section: Discussionsupporting

confidence: 55%

Involvement of HIF-1α activation in the doxorubicin resistance of human osteosarcoma cells

2014

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“…mTOR increases both protein synthesis and lipogenesis through mechanisms including enzyme phosphorylation and transcriptional activation of EIF1A (38) and SREBP1 (39)(40)(41). In contrast, mesenchymal states are associated with increased c-Myc expression and HIF1A, which have been shown to drive a glycolytic profile (42,43). Regardless of the nature or mechanism of action for the metabolic variation we observed, our data provide valuable predictive utility and thereby inform clinical evaluation of a variety of metabolic inhibitors such as MCT and glutaminase inhibitors currently undergoing phase I testing across a variety of tumor indications.…”

Section: Discussionmentioning

confidence: 99%

Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

Daemen¹,

Peterson²,

Sahu³

et al. 2015

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

304

287

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Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors.metabolite profiling | metabolic subtypes in PDAC | glycolysis | lipid synthesis | biomarkers for metabolic inhibitors M etabolic reprogramming during tumorigenesis is an essential process in nearly all cancer cells. Tumors share a common phenotype of uncontrolled cell proliferation and must efficiently generate the energy and macromolecules required for cellular growth. The first example of metabolic reprogramming was discovered more than 80 y ago by Otto Warburg: tumor cells can shift from oxidative to fermentative metabolism in the course of oncogenesis (1). More recently, there has been a resurgence of interest in targeting cancer metabolism (2-4) because it may not only be effective in inhibiting tumor growth, but may also provide a therapeutic window (5, 6). For example, inactivation of lactate dehydrogenase-A (LDHA), an enzyme that catalyzes the final step of aerobic glycolysis, thereby reducing pyruvate to lactate, decreases tumorigenesis and induces regression of established tumors in mouse models of lung cancer driven by oncogenic KRAS or epidermal growth factor receptor (EGFR) while minimally affecting normal cell function (7). The finding that cancers have altered metabolism has prompted substantial investigation, both preclinically and in clinical trials, of several metabolically targeted agents, including those that elevate reactive oxygen species (ROS) or block glycolysis, lipid synthesis, mitochondrial function, and glutamine synthesis pathways (8).The identification of distinct metabolic reprogramming events or metabolic subtypes in cancer may inform patient selection for investigational...

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“…HIF-1α-dependent activation of TGF-β1 signaling and upregulation of survivin also contributes to EMT and resistance to apoptosis, respectively, in human NSCLC cells [79,80]. Recently, hypoxia-induced metastasis has been linked to activation of the c-Myc pathway, upregulation of membrane-type 4 MMP via Slug and induction of LOX, which acts both extracellularly to stabilize collagen deposition and intracellularly to foster EMT thru stabilization of Snail [75,[81][82][83].…”

Section: Inflammation Creates a Hypoxic Microenvironmentmentioning

confidence: 99%

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

Heinrich

Walser

Krysan

et al. 2011

Cancer Microenvironment

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The inflammatory tumor microenvironment (TME) has many roles in tumor progression and metastasis, including creation of a hypoxic environment, increased angiogenesis and invasion, changes in expression of microRNAs (miRNAs) and an increase in a stem cell phenotype. Each of these has an impact on epithelial mesenchymal transition (EMT), particularly through the downregulation of E-cadherin. Here we review seminal work and recent findings linking the role of inflammation in the TME, EMT and lung cancer initiation, progression and metastasis.Finally, we discuss the potential of targeting aspects of inflammation and EMT in cancer prevention and treatment.

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HIF-1α Confers Aggressive Malignant Traits on Human Tumor Cells Independent of Its Canonical Transcriptional Function

Cited by 49 publications

References 51 publications

Involvement of HIF-1α activation in the doxorubicin resistance of human osteosarcoma cells

Involvement of HIF-1α activation in the doxorubicin resistance of human osteosarcoma cells

Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

The Inflammatory Tumor Microenvironment, Epithelial Mesenchymal Transition and Lung Carcinogenesis

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