Drug Discovery
reported to be constitutively active whereas PKM2 is present in embryonic and adult stem cells and controlled by various regulator mechanisms. It has been widely reported that PKM2 is also over- expressed in many tumour cells and a switch from PKM1 to PKM2 expression in cancer has been pro- posed2,28,89. The PKM2 isoform is generated by alternative splicing of exon 10 on the PK gene, an event shown to be under myc regulation suggesting a potential oncogenic driver for PKM2 expression in cancers30,112. However, the PKM2 expression hypothesis has been recently questioned in a study which used mass-spectroscopy to identify PK iso- forms and reported that PKM2 is expressed in nor- mal tissues as well as cancers and that PKM1 had low expression in cancers as well as in normal tis- sue113. Although the ratio of PKM2 to PKM1 expression was similar between cancers and matched normal tissues, the actual amounts of each protein were much higher in the tumours sug- gesting that both PKM2 and PKM1 were over- expressed in tumour samples113.
Studies in which PKM2 is knockdown or replaced
by PKM1 have shown that PKM2 is involved in tumour progression and that PKM2 expression con- fers a tumourigenic advantage over PKM1 expres- sion89. However, it has also been shown that while PKM1 can efficiently promote glycolysis, PKM2 is characteristically found in an inactive state and is inefficient in promoting glycolysis2,28,89,114. PKM2 exists in two possible conformations, an inactive dimer and more active tetramer (Figure 3). Oncogenic tyrosine kinases (eg fibroblast growth factor receptor kinase) have been found to promote the formation of the inactive dimer via the phos- phorylation of tyrosine 705 on PKM290,114. PKM2 activity has also been shown to be negatively regu- lated by acetylation induced by high levels of glu- cose115. This data collectively suggests that expres- sion of PKM2 in cancer could actually decrease gly- colytic flux. While this was initially thought to be counterintuitive, when considered in terms of the cancer cell’s metabolic needs, a mechanism which slows glycolysis is actually potential advantageous. By slowing glycolytic flux the cancer is able to obtain building block, co-factors and precursors by
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Fast. Accurate. EASY. 70 Drug Discovery World Fall 2011
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