Friday Science Review: March 16, 2012
March 16, 2012
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I have spent much of this week looking into cancer metabolism, where the recent partnership successes of Forma and fund raising by Agios have shown how hot this area has become. Many cancer cells it turns out switch their metabolism to aerobic glycolysis, a phenomenon known as the Warburg effect. An important regulator of the switch to glycolytic metabolism is the transcription factor HIF-1 (hypoxia inducible factor 1), which, in response to low oxygen conditions or cytokines, growth factors and ROS amongst others up-regulates a whole host of elements involved in stimulating glycolytic flux, including the glycolysis enzymes and regulators, as well as glucose transporters etc.
The cellular rationale above seems clear, in low oxygen conditions cells up-regulate their ability to carry out anaerobic energy production. However, coincidentally, the recent research led by Dr Michael Ohh at the University of Toronto, reveals an interesting new facet to the adaptations: HIF-1 also increases the expression of Caveolin-1 (CAV1), a structural component of caveolae – small flask shaped invaginations in the plasma membrane that have roles in cell signaling and endocytosis. Their research shows that the HIF-1 induced CAV-1 expression leads to increased caveolae on the cell surface and significantly, as a result, increased activation of the EGF signaling pathway even in the absence of ligand due to dimerization of EGF receptors within the caveolae. HIF-1 dependent up-regulation of CAV-1 thereby enhanced the oncogenic potential of tumour cells and increased tumour cell proliferation.
HIF-1 over-expression is commonly seen in tumors, either due to hypoxic tumor conditions, or due to aberrant regulation resulting from mutations in upstream tumor suppressors such as TSC2, PTEN, p53, and VHL and this new finding emphasizes the complexity of the changes seen in cancer signaling and metabolism. The enhancement of glycolysis and the increase in oncogenic potential from ligand independent EGF signaling are related, but how does one attempt to integrate these very different changes? Are changes like the ligand independent EGF signaling encouraging the switch to glycolysis, or is it glycolysis itself that is favorable (for which there are multiple opinions on the possible cellular rationale)?
- Lung adenocarcinoma of never smokers and smokers harbor differential regions of genetic alteration and exhibit different levels of genomic instability. PLoS One. British Columbia Cancer Research Centre
- Mechanistic Insight into the Microtubule and Actin Cytoskeleton Coupling through Dynein-Dependent RhoGEF Inhibition. Molecular Cell. University of Toronto
- Cell-Type Specific Roles for PTEN in Establishing a Functional Retinal Architecture. PLoS One. University of Calgary
- HIV-1 Promotes Intake of Leishmania Parasites by Enhancing Phosphatidylserine-Mediated, CD91/LRP-1-Dependent Phagocytosis in Human Macrophages. PLoS One. Université Laval