Last week Vicki introduced a paper by Preston et al. that showed that Folliculin also influences hypoxia-inducible factor (HIF) signalling. This pathway regulates a myriad of different genes that are involved in angiogenesis, erythropoiesis, cell survival and metastasis- so it is completely conceivable that it has a significant role to play in the development of cancer.
In addition to this, the authors also analysed the activity of a series of metabolic enzymes involved in glucose metabolism, fatty acid oxidation and the Krebs cycle, and saw that FLCN-null UOK257 cells favoured glycolysis over lipid metabolism. What is particularly interesting about this observation is that this altered metabolic state happens to parallel a phenomenon known as the Warburg effect.
The Warburg effect was first postulated by Otto Warburg in 1924, and describes how most cancer cells predominantly produce energy by a high rate of glycolysis, instead of from the oxidation of pyruvate in mitochondria. However, glycolysis produces considerably less ATP than mitochondrial oxidative phosphorylation- so why do cancer cells adopt this process? Two hypotheses have been put forward to explain this phenomenon. Firstly, glycolysis produces many of the metabolites and building blocks required for the rapid cell growth of cancers. Secondly, pyruvate, the product of glycolysis, is a scavenger of hyperoxide thereby protecting these cells from the oxidative stress that is a consequence of this rapid growth. A paper written by Kim et al. nicely summarises these points.
The Warburg effect has now become widely accepted and has even been used as a marker to identify and diagnose cancerous cells, through monitoring the uptake of a radioactive hexokinase substrate. As for BHD syndrome, this phenomenon could also be manipulated in order to develop a variety of anti-cancer drugs.
This is exactly what Preston et al. set about doing by testing the glucose dependency of FLCN-null cells by competitively blocking glycolysis with a glucose analogue called 2-deoxyglucose. What they saw was that, consistent with a glycolytic requirement, the FLCN-null UOK257 cells were selectively inhibited by 2-deoxyglucose. This result will certainly lead to many new avenues of research, and it will be particularly interesting to explore the role of Folliculin further, not just in signalling pathways, but also in cell metabolism.
- Kim, H., Kim, T., Kim, E., Park, J., Park, S., Joo, H., & Kim, H. (2009). The Mitochondrial Warburg Effect: A Cancer Enigma Interdisciplinary Bio Central, 1 (2), 1-7 DOI: 10.4051/ibc.2009.2.0007
- Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, & Tee AR (2011). Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 30 (10), 1159-73 PMID: 21057536