Targeting cancer cell metabolism as a therapeutic strategy

Q Science (General);RC0254 Neoplasms. Tumors. Oncology (including Cancer)

Chaneton, Barbara Julieta ; Gottlieb, Eyal

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: cancer, metabolism, metabolomics;   

Others  :  http://theses.gla.ac.uk/5762/1/2014chanetonphd.pdf

来源: University of Glasgow

【 摘 要 】

In the past 15 years the field of cancer metabolism has burst providing vastquantities of information regarding the metabolic adaptations found in cancercells and offering promising hints for the development of therapies that targetmetabolic features of cancer cells.By making use of the powerful combination of metabolomics and 13C-labelledmetabolite tracing we have contributed to the field by identifying amitochondrial enzymatic cascade crucial for oncogene-induced senescence (OIS),which is a tumour suppressive mechanism important in melanoma, linking in thisway OIS to the regulation of metabolism.Furthermore, we have identified the dependency on glutamine metabolism as animportant adaptation occurring concomitantly with the acquisition of resistanceto vemurafenib (BRAF inhibitor) in melanoma, which opens the possibility tocombine therapies targeting glutamine metabolism with BRAF inhibitors, in orderto overcome or avoid the onset of resistance in melanoma.Using the same strategy we have discovered an important mechanism of interregulationbetween glycolysis and amino acid metabolism, identifying theglucose-derived amino acid serine as an activator of the main isoform ofpyruvate kinase present in cancer cells, PKM2. In addition, we provide newinsights into the mechanism of allosteric regulation of this complex protein and abetter understanding of the way it regulates central carbon metabolism.In summary, our results open new possibilities for the development of cancertherapies that manipulate metabolic adaptations found in cancer cells in orderto kill them specifically or halt their growth.