Abstract 223: Targeting PDK-1 and EGFR by human umbilical cord blood stem cells reverses Warburg effect in glioblastoma multiforme

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.223-223
• Main Authors: Velpula, Kiran Kumar, Bhasin, Arnima, Dasari, Venkata Ramesh, Asuthkar, Swapna, Dinh, Dzung H., Rao, Jasti S., Tsung, Andrew J.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-223

Glioblastoma multiforme (GBM) is the most aggressive and incurable brain tumor in adults. The overexpression of epidermal growth factor receptor (EGFR) in GBM is identified as typical oncogenic signature. Due to the functional diversity of proteins that are phosphorylated or complexed with EGFR, it unsurprising that EGFR is involved in multiple interconnected signaling pathways. In GBM, hypoxia drives aggression and malignancy through glycolysis as opposed to oxidation of pyruvate in the mitochondria. This phenomenon, termed the Warburg effect, has a prominent role in oncogenesis. In the present study, we show that hypoxia induces pyruvate dehydrogenase kinase 1 (PDK-1) expression, which in turn increases the expression of EGFR and hypoxia inducing factor 1 alpha (HIF-1α) in cell lines derived from human GBM. PDK-1 is a HIF-1-regulated gene, and our data suggested that hypoxia-induced PDK-1 expression may promote EGFR activation, thus sustaining a feed-forward loop for malignant progression. PDK-1 and EGFR knockdown, using respective shRNAs or human umbilical cord blood stem cells (hUCBSC), lowers PDK-1-EGFR phosphorylation and decreases HIF-1α expression, which reverts the Warburg phenotype of GBM leading to inhibition of tumor- growth and invasion. Clinically, expression of PDK1, EGFR, and HIF-1α were elevated in GBM specimens when compared to normal brain tissues. Collectively, our studies indicate PDK-1 as a key mediator of tumor growth in GBM and that targeting PDK-1 and its associated molecules such as HIF-1α and EGFR may prove promising for inhibition of the Warburg effect in human GBMs. Citation Format: Kiran Kumar Velpula, Arnima Bhasin, Venkata Ramesh Dasari, Swapna Asuthkar, Dzung H. Dinh, Jasti S. Rao, Andrew J. Tsung. Targeting PDK-1 and EGFR by human umbilical cord blood stem cells reverses Warburg effect in glioblastoma multiforme. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 223. doi:10.1158/1538-7445.AM2013-223