This group also revealed that PGE2 is the main PG produced in mouse pancreatic tissue

of bioenergetic Varlitinib metabolism standpoint. During this scenario, stromal cells, which are subjected to oxidative stress and switch to a glycolysis-based metabolism, can also generate high levels of lactate and ketone bodies that initiate the oxidative phosphorylation process. This metabolic circuitry crosstalk, which closely resembles the well-known lactate shuttle bridging in cancer cells and stroma, is called “reverse Warburg effect”. Cancer cells have been shown to secrete high levels of hydrogen peroxide,15 by which they can attain a local oxidative PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19808981 microenvironment. Stromal cells tend to react to such oxidative conditions through enhancing their autophagic flux as well as activation of hypoxia-inducible factor 1, which can in return trigger degradation of Cav-1 and also activate several important genes related to glycolysis and result in production of lactic acids and ketone bodies. These byproducts can be taken up by cancer cells through MCT1 to fuel oxidative phosphorylation.16 One of the key elements of Warburg effect was shown to be HIF-l, whose activation in malignancies can increase the transcription of many genes involved in glucose metabolism, apoptosis resistance, invasion, metastasis and angiogenesis. It seems that the activation of glycolysis can favor the biosynthesis process in conformity with cancer, supporting cell proliferation. For example, glycolytic metabolites such as glucose 6-phosphate, 3phosphoglycerate, phosphoenolpyruvate and pyruvate are key precursors in the biosynthesis of several amino acids while dihydroxyacetone phosphate is the key precursor of glycerol, a necessary metabolite for the synthesis of lipids.17 Hence, the hypoxia and HIF-1 will be briefly 152 BioImpacts, 2013, 3, 149-162 discussed in the following sections. Hypoxia and HIF-1 Hypoxia epitomizes the unique characteristic of all solid tumors, in which an imbalance between enhanced oxygen consumption by cancer cells and insufficient oxygen delivery from the aberrant tumor vasculature appear to be the main reason for such phenomenon though it happens even in the presence of oxygen. Given the fact that the metabolism of glucose in cancer cells is mainly through glycolysis, the acidic byproducts are pumped out of the cytoplasm resulting in pH dysregulation within the TME; that is, alkalinized intracellular fluid and acidified extracellular fluid. Such transformed metabolism in cancer cells is reported to enhance the resistance of the cancer cells to radiation and chemotherapy.18 The Warburg effect and the hypoxia are associated with activation of HIF-1 that is a transcription factor critically involved in cellular responses to hypoxia and tumor progression and modulate the expression of a large number of genes within TME under hypoxic conditions. As a heterodimeric protein comprised of an aryl hydrocarbon receptor and a nuclear translocator, the subunit of HIF1 is regulated by oxygen concentrations. Accordingly, there exist evidences showing that the HIF-1 is overexpressed in various malignancies. It is associated with a range of genetic alterations such as loss of function of tumor suppressor genes along with increased activity of some oncogenes.19-21 HIF-l has been being considered as one of the attractive oncomarkers for the development of novel cancer therapeutics. Copyright 2013 by Tabriz University of Medical Sciences pH dysregulation in tumor microenvironment Inhibitor Mechanism of action : Classical views of chromosome structure The segreg