However, early on in evolution, oxygen sensing has emerged, as a central control mechanism Peptide 17 cost of energy metabolism and vasculogenesis. At the heart of this regulatory system is the Hypoxia-Inducible Factor, HIF, which controls, among other gene products, the expression of

VEGF-A and Angiopoïetin-2, two key angiogenic factors in vertebrates. This finding has placed the hypoxia-signaling pathway at the forefront of nutritional control. HIF controls glycolysis, intracellular pH (pHi), angiogenesis, cell migration and invasion, and so has become recognized as a strong promoter of tumor growth. We will highlight some of the HIF-induced gene products that participate in tumor adaptation, resistance and progression in a nutrient-depleted and acidic microenvironment. First we will demonstrate that the two HIF-induced ‘BH3-only’-proteins (BNIP3, BNIP3L/NIX), in contrast to current belief, do not trigger cell death but, by inducing macro-autophagy, stimulate selleck kinase inhibitor tumor cell survival. Second, we will show how tumor cells by expressing two HIF-dependent membrane-bound carbonic anhydrases, CAIX and CAXII, acidify the extracellular milieu, and ensure a more alkaline intracellular pH favoring migration, survival and growth in a hostile acidic microenvironment.

Third, HIF-induced glycolysis in most hypoxic tumor cells is essential to ensure maintenance of ATP levels for growth and cell survival. Two MonoCarboxylate Transporters MCT-1 and MCT-4, stabilized in the plasma membrane by the common chaperon basigin/CD147, play a key role in cancer metabolism. We propose that appropriate exploitation of these HIF-regulated proteins and new validated cancer targets, which control exacerbated tumor metabolism and intracellular pH, will be at the forefront of anti-cancer therapy. O8 Identifying New Anti-Cancer Therapeutics Using Synthetic Lethality Amato Giaccia 1 , Sandra Turcotte1, Patrick Sutphin1, William Denny2, Michael Hay2, Denise Chan1 1 Radiation Oncology, Stanford University, Stanford, CA, USA, 2 Experimental Therapeutics, University of Auckland, Auckland, New Zealand

Synthetic lethality results when two nonallelic mutations that by themselves are not lethal, answer in cell death when combined. To screen for small molecules that acted in a synthetic lethal manner to the loss of VHL, we needed C-X-C chemokine receptor type 7 (CXCR-7) a means of tracking cell growth in microwell plates when exposed to a library of small molecules. Renal carcinoma cell lines with naturally occurring VHL mutations and their genetically matched wild-type VHL counterparts were stably labeled with enhanced yellow fluorescent protein (EYFP). Cells were then seeded onto 384-well plates and allowed to attach overnight. Baseline fluorescence readings were obtained and a compound library was added at a concentration of 5 μM. Fluorescence intensity was read once a day for four days. An increase in fluorescence intensity was used as a surrogate marker for cell growth.