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Title: Pyruvate dehydrogenase kinase (PDK) as a novel anti-cancer therapeutic target
Author: Yeluri, Sashidhar
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Cancers preference for glycolysis, with down-regulation of mitochondrial respiration, also known as the 'Warburg effect', provides a unique cancer target by modulation of mitochondrial respiration. We have examined the key regulators of glycolysis and mitochondrial respiration in colorectal cancers (CRC), to investigate its influence on outcome, and identify novel targets for anti-cancer therapy. METHODS: Antibody specificity was confirmed by western blotting. Tissue micro-arrays incorporating 280 GRG were constructed using archival colorectal tissue from the medical research council (MRC) CLASICC trial, and probed by immunohistochemistry for markers of glycolysis (HIF1a, LDH5, HK2), and oxidative phosphorylation (PDK isoforms 1-4, PDC subunits E1a, E2). SPDPK1 was also investigated due to its key role in the PISK-Akt pathway. Expression levels were scored semi-quantitatively, and compared to clinicopathological and 5-year survival data. RESULTS: Poorly differentiated tumours showed a significantly higher expression of HIF1 a (p=0.028). Higher levels of HIF1α associated significantly with lymph nodal involvement (p=0.027). High PDKS (p=0.008, HR=2.16, 95% Cl: 1.22, S.82), low PDHE1 a (p<0.001, HR=2.46, 95% Cl: 1.57, S.86) and high HIF1 a (p=0.001 , HR=2.61 , 95% Cl: 1.49,4.57) levels were independent predictors of worse 5-year disease free survival. High PDKS (p=0.OS7, HR=S.04, 95% Cl: 1.07, 8.62) and HIF1 a (p=0.041, HR=2.69, 95% Cl: 1.04, 6.9S) levels also predicted for increased 5-year distant recurrence, DISCUSSION: CRC demonstrating Warburg effect display aggressive biology, and are associated with significantly worse survival. The PDH/PDK system, which is integral to the Warburg effect, associates significantly with cancer survival and spread. The study identifies the potential for further investigation into PDKS as an attractive anti cancer target.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available