This morning I was taking a breather from work to catch up on my Science and Nature reading.
There was a most intriquing Letter to Nature from Lu and colleagues at MD Anderson, describing how PKM2 (pyruvate kinase muscle) may not just have an established role to play in metabolism (via the Warburg effect in glycolysis), but how it may also have important non-metabolic functions in tumour formation and growth:
“Here we demonstrate, in human cancer cells, that epidermal growth factor receptor (EGFR) activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of b-catenin.”
In other words, it directly contributes to gene transcription for cancer cell proliferation.
From a scientific point of view, understanding the process of tumorigenesis, ie tumour formation and growth, is critical to figuring out how to stop it. If we know precise elements of the process, then a more targeted and focused approach can be used in the clinic based on a solid rationale that has a better chance of success. That’s much more sensible than literally throwing mud at walls randomly and hoping something sticks!
It is well known that EGFR activation and PKM2 expression are instrumental in tumorigenesis, but the question is how and what:
“These findings reveal that EGF induces b-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted b-catenin transactivation, cell proliferation and tumorigenesis.”
The researchers also went onto to note that:
“PKM2-dependent b-catenin transactivation is instrumental in EGFR promoted tumour cell proliferation and brain tumour development. In addition, positive correlations have been identified between c-Src activity, b-catenin Y333 phosphorylation and PKM2 nuclear accumulation in human glioblastoma specimens.”
The basis for this idea came from an analysis of samples from tumours of patients with glioblastoma (n=84) who had been previously treated with radiation and chemotherapy after surgery.
They observed that patients who had low beta-catenin Y333 phosphorylation or low expression of PKM2 in the nucleus (n=28 each) had a median survival of 185 weeks and 130 weeks, respectively.
However, median survival decreased for those who had high levels of beta-catenin phosphorylation or nuclear PKM2 expression (n=56 each) to 69.4 weeks and 82.5 weeks, respectively.
Overall, there were a number of important findings, as explained in MD Anderson’s excellent press release describing the work:
“PKM2-dependent beta-catenin activation is instrumental in EGFR-promoted tumor cell proliferation and brain tumor development.
c-Src activity, beta-catenin Y333 phosphorylation, and PKM2 nuclear accumulation are positively correlated in human glioblastoma (GBM) specimens.
Levels of beta-catenin phosphorylation and nuclear PKM2 are correlated with grades of glioma malignancy and prognosis.”
Significance of these results
These results are not only unexpected, they also have some future practical implications, becuase EGFR inhibitors have not proven useful therapeutically in GBM:
- New biomarkers: c-Src-dependent beta-catenin Y333 phosphorylation levels could potentially be used as a biomarker for selecting patients for treatment.
- New treatment approaches: Src inhibitors (eg dasatinib, bosutinib, saracatinib) in an appropriately selected patient population most likely to respond, as opposed to allcomer trials, where the inherent tumour heterogeneity hides the positive treatment effect of responders.
This is an important article and well worth taking a few minutes out of your day to read.
Yang, W., Xia, Y., Ji, H., Zheng, Y., Liang, J., Huang, W., Gao, X., Aldape, K., & Lu, Z. (2011). Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation Nature DOI: 10.1038/nature10598