Abstract 1809: PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation
| Autor: | Kristina Diepold, Susanne Bobrovich, Arefeh Rouhi, Thomas Seufferlein, Ninel Azoitei, Alexander Becher, Konrad Steinestel |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:1809-1809 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2017-1809 |
| Popis: | Initially identified as a molecule that catalyzes the phosphorylation from phosphoenolpyruvate to pyruvate in the final step of glycolysis, the M2 isoform of pyruvate kinase (PKM2) was recently reported to have a central role in the metabolic reprogramming of cancer cells as well as participating in the regulation of apoptosis and proliferation. In this study, we have identified PKM2 as a crucial molecule for progression of pancreatic cancer in which tumor microenvironment has been reported to be highly hypoxic. Our data show moderate to strong PKM2 expression in all examined human pancreatic adenocarcinoma samples. Depletion of PKM2 was associated with impaired proliferation and augmented tumor cell death in vitro, while the in vivo tumor xenograft experiments revealed a close association between impaired tumor growth and decreased blood vessel formation. Furthermore, abrogation of PKM2 prevented hypoxia-mediated HIF-1alpha accumulation and HIF-1alpha promoter activity, which negatively impacted VEGF secretion by pancreatic cancer cells deprived of oxygen. Interestingly, PKM2 expression arrest was also mirrored by impaired hypoxia-driven promoter activity of NF-kappaB which also drives the transcription of VEGF. Ectopic expression of p65 restored VEGF transcription after PKM2 ablation inferring that the kinase regulates VEGF via NF-kappaB/p65 subunit. Altogether, our study suggests that in hypoxic pancreatic tumors PKM2 interferes both with NF-kappaB/p65 and HIF-1alpha activation that ultimately triggers VEGF-A secretion and subsequent blood vessel formation. Citation Format: Ninel Azoitei, Alexander Becher, Konrad Steinestel, Arefeh Rouhi, Kristina Diepold, Susanne Bobrovich, Thomas Seufferlein. PKM2 promotes tumor angiogenesis by regulating HIF-1alpha through NF-kappaB activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1809. doi:10.1158/1538-7445.AM2017-1809 |
| Databáze: | OpenAIRE |
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