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IBA Publikation
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DATUM, UNTERSCHRIFT / DATE, SIGNATURE
BANK AUSTRIA CREDITANSTALT, WIEN (IBAN AT04 1100 0006 2280 0100, BIC BKAUATWW), DEUTSCHE BANK MÜNCHEN (IBAN DE16 7007 0024 0238 8270 00, BIC DEUTDEDBMUC)
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IBA Publikation, pp. 312-231, 2008/09/01
Reprogramming of carbohydrate metabolism is a hallmark of tumor cells which have a high demand of energy as well as of precursors for DNA synthesis and other biosynthetic processes to grow and survive. Such cells preferentially utilize the glycolytic pathway to achieve these demands. The important role of glycolysis for tumorigenesis is underlined by studies providing evidence for a direct link between cancer genes and the reprogramming of this pathway. Thus, several oncoproteins have been shown to target glycolytic enzymes. One important target is pyruvate kinase isoenzyme M2 (M2-PK), which is directly targeted by the high-risk human papillomavirus type-16 E7 oncoprotein. M2-PK regulates the rate limiting step at the end of the glycolytic pathway in tumor cells. The aim of the present study was to investigate whether specific inhibitors of M2-PK are able to effect tumor cell proliferation and apoptosis. To do this we designed specific inhibitors of M2-PK by molecular engineering of M2-PK-binding peptide aptamers. We demonstrate that these combinatorial proteins specifically bind to M2-PK, block its enzymatic activity and inhibit tumor cell proliferation. Thus, here we rationally developed the first isotype-specific inhibitors of M2-PK, a glycolytic key regulator in tumor cells, and demonstrated that a selective intervention in the fine regulation of M2-PK may interfere with tumor cell proliferation.
Keywords: Tumor Metabolism Peptide Aptamer Proliferation Pyruvate kinase