Two papers in Nature this week have identified a key player in this process (subscription required, summary here). The protein is the M2 isoform of pyruvate kinase (PKM2), which is the fetal form of this protein. PKM2 is also expressed in tumour cells, while normal adult tissue expressed the M1 form exclusively. These papers show that PKM2 is inhibited by phosphotyrosine affecting cellular metabolism. One of the papers suggests:
"this mechanism evolved to ensure that fetal tissues only use glucose for growth when they are activated by appropriate growth factor receptor protein-tyrosine kinases. Cancer cells, by re-expressing PKM2, acquire the ability to use glucose for anabolic processes."
In other words, re-activation of PKM2 allows the rapid growth associated with cancer. This was shown a variety of ways, by measuring glycolysis rate, cell proliferation and glucose incorporation into lipids after PKM2 knockdown/re-introduction or phosphatase inhibition (increasing the available phospho-tyrosine for PKM2 inhibition).
To further implicated PKM2 in cancer biology, the second paper showed that introduction of the M1 form into cancer cell lines increased their oxygen consumption and decreased lactate production (consistant with increased oxidative phosphorylation). Additionally, mice injected with cancer cells expressing the M1 isoform had slower tumour development, fewer tumours when they did develop and smaller tumours compared to M2 cell injections.
Both of these papers identify a key player in the Warburg effect, PKM2, and show it contributes significantly to tumorigenesis. Because PKM2 was found in all the tumour cells the authors analyzed, this unique biology could be exploited as a broad therapeutic target.
- Heather R. Christofk, Matthew G. Vander Heiden, Ning Wu, John M. Asara & Lewis C. Cantley. Nature 452, 181-186(13 March 2008) doi:10.1038/nature06667
- Heather R. Christofk, Matthew G. Vander Heiden, Marian H. Harris, Arvind Ramanathan, Robert E. Gerszten, Ru Wei, Mark D. Fleming, Stuart L. Schreiber & Lewis C. Cantley Nature 452, 230-233(13 March 2008) doi:10.1038/nature06734