Proliferation-Independent Control of Tumor Glycolysis by PDGFR-Mediated AKT Activation

Ran, Cong; Liu, Huan; Hitoshi, Yasuyuki; Israel, Mark A.

doi:10.1158/0008-5472.can-12-2460

Cited by 41 publications

(43 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Already established uPAR‐mediated pathways include an integrin‐dependent uPAR association with the four IL‐TKR systems EGFR, IGFR, PDGFR and MET . Such IL‐TKRs also regulate glucose uptake and glycolysis in many cell types and in cancer cells . Dependent on the cell type, different integrins mediate uPAR interaction with partner molecules.…”

Section: Resultsmentioning

confidence: 99%

uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells

et al. 2017

View full text Add to dashboard Cite

In this manuscript, we show the involvement of the uPA/uPAR system in the regulation of aerobic glycolysis of melanoma cells. uPAR over-expression in human melanoma cells controls an invasive and glycolytic phenotype in normoxic conditions. uPAR down-regulation by siRNA or its uncoupling from integrins, and hence from integrin-linked tyrosine kinase receptors (IL-TKRs), by an antagonist peptide induced a striking inhibition of the PI3K/AKT/mTOR/HIF1α pathway, resulting into impairment of glucose uptake, decrease of several glycolytic enzymes and of PKM2, a checkpoint that controls metabolism of cancer cells. Further, binding of uPA to uPAR regulates expression of molecules that govern cell invasion, including extracellular matrix metallo-proteinases inducer (EMPPRIN) and enolase, a glycolytyc enzyme that also serves as a plasminogen receptor, thus providing a common denominator between tumor metabolism and phenotypic invasive features. Such effects depend on the α5β1-integrin-mediated uPAR connection with EGFR in melanoma cells with engagement of the PI3K-mTOR-HIFα pathway. HIF-1α trans-activates genes whose products mediate tumor invasion and glycolysis, thus providing the common denominator between melanoma metabolism and its invasive features. These findings unveil a unrecognized interaction between the invasion-related uPAR and IL-TKRs in the control of glycolysis and disclose a new pharmacological target (i.e., uPAR/IL-TKRs axis) for the therapy of melanoma.

show abstract

Section: Resultsmentioning

confidence: 99%

uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…RTK-PI3K-Akt-mTOR signaling cascade is a frequently altered pathway in cancer. PDGFR signaling regulates glycolysis in glioma-derived tumor stem-like cells through the activation of Akt [98]. PI3K-Akt-mTOR signaling is indispensable for the EGFR-mediated regulation of aerobic glycolysis in lung cancer cells [99].…”

Section: Regulation Of Glycolysis In Tumorsmentioning

confidence: 99%

The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

et al. 2016

View full text Add to dashboard Cite

Metabolic change is one of the hallmarks of tumor, which has recently attracted a great of attention. One of main metabolic characteristics of tumor cells is the high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in glycolysis pathway than that in tricarboxylic acid cycle. The molecular mechanism of a high glycolytic flux in tumor cells remains unclear. A large amount of intermediates derived from glycolytic pathway could meet the biosynthetic requirements of the proliferating cells. Hypoxia-induced HIF-1α, PI3K-Akt-mTOR signaling pathway, and many other factors, such as oncogene activation and tumor suppressor inactivation, drive cancer cells to favor glycolysis over mitochondrial oxidation. Several small molecules targeting glycolytic pathway exhibit promising anticancer activity both in vitro and in vivo. In this review, we will focus on the latest progress in the regulation of aerobic glycolysis and discuss the potential targets for the tumor therapy.

show abstract

“…On the contrary, pervasive metabolic signatures have been identified, particularly the dependence upon glycolysis rather than oxidative phosphorylation (OXPHOS) with elevated lactate production regardless of oxygen availability. This bioenergetic state, when associated with increased glucose metabolism, results in tumorigenesis and tumor progression and a phenomenon termed the Warburg effect (1)(2)(3)(4)(5)(6). The end result is such that despite functionally complex pathways, convergence occurs to some degree at the mitochondrial level.…”

Section: Introductionmentioning

confidence: 99%

Combined Targeting of PDK1 and EGFR Triggers Regression of Glioblastoma by Reversing the Warburg Effect

et al. 2013

View full text Add to dashboard Cite

Glioblastoma multiforme is the most aggressive primary brain tumor in adults. Overexpression of the EGF receptor (EGFR) is recognized as a widespread oncogenic signature in glioblastoma multiforme, but the complexity of its contributions is not fully understood, nor the most effective ways to leverage anti-EGFR therapy in this setting. Hypoxia is known to drive the aggressive character of glioblastoma multiforme by promoting aerobic glycolysis rather than pyruvate oxidation carried out in mitochondria (OXPHOS), a phenomenon termed the Warburg effect, which is a general feature of oncogenesis. In this study, we report that hypoxia drives expression of the pyruvate dehydrogenase kinase (PDK1) and EGFR along with the hypoxiainducing factor (HIF)-1a in human glioblastoma multiforme cells. PDK1 is a HIF-1-regulated gene and our findings indicated that hypoxia-induced PDK1 expression may promote EGFR activation, initiating a feedforward loop that can sustain malignant progression. RNAi-mediated attenuation of PDK1 and EGFR lowered PDK1-EGFR activation and decreased HIF-1a expression, shifting the Warburg phenotype to OXPHOS and inhibiting glioblastoma multiforme growth and proliferation. In clinical specimens of glioblastoma multiforme, we found that immunohistochemical expression of PDK1, EGFR, and HIF-1a were elevated in glioblastoma multiforme specimens when compared with normal brain tissues. Collectively, our studies establish PDK1 as a key driver and candidate therapeutic target in glioblastoma multiforme. Cancer Res; 73(24); 7277-89. Ó2013 AACR.

show abstract

Proliferation-Independent Control of Tumor Glycolysis by PDGFR-Mediated AKT Activation

Cited by 41 publications

References 50 publications

uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells

uPA/uPAR system activation drives a glycolytic phenotype in melanoma cells

The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

Combined Targeting of PDK1 and EGFR Triggers Regression of Glioblastoma by Reversing the Warburg Effect

Contact Info

Product

Resources

About