September-October 2011, Volume 8, Issue 5
Into Thin Air: New Insights Into the Role of Hypoxia-Inducible Factor in Cancer and Ischemic Diseases
Published on: September 01, 2011
Drs. Cheng and Linenberger indicated no relevant conflicts of interest.
Luo W, Hu H, Chang R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145:732-744.
Rey S, Luo W, Shimoda LA, et al. Metabolic reprogramming by HIF-1 promotes the survival of bone marrow-derived angiogenic cells in ischemic tissue. Blood. 2011;117:4988-4998.
The normal cellular response to low oxygen state and tissue ischemia includes activation of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that shifts metabolism toward non-oxidative glycolysis and triggers adaptive mechanisms that affect cell survival, migration, adhesion, and extracellular signals. Notably, many cancer cells preferentially utilize glycolytic metabolism, even in oxygen-abundant states, and this feature serves as the mechanistic basis of positron-emitting tomography imaging of glucose-avid tumors with FDG. Otto Warburg hypothesized in 1924 that cancer cell glycolysis (referred to as the “Warburg effect”) underlies a critical pathobiological function in tumorigenesis. Indeed, activation of HIF-1 in cancer cells induces genes encoding proteins involved in invasion, metastasis, and angiogenesis. Despite this growing knowledge of HIF-1, many key molecular interactions remain undefined. Two publications from the laboratory of Gregg Semenza at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins provide important new insights into HIF-1-associated dysregulation in tumor cells and biochemical approaches of manipulating HIF-1 in angiogenic cells to enhance their ability to salvage ischemic tissue.
Luo and colleagues explored the regulatory pathways responsible for the Warburg effect in cultured tumor cell lines. Because the M2 isoform of pyruvate kinase (PK), the enzyme responsible for the final step of glycolysis, is preferentially expressed in tumor cells, they focused on how PKM2 interacts with the oxygen-regulated HIF-1α subunit of the HIF-1 heterodimer and on HIF-1 transcriptional activity. In a series of elegant biochemical experiments they showed that PKM2 is a HIF-1 target gene, PKM2 directly interacts with HIF-1α to enhance DNA binding and HIF-1 transcriptional activity, and PKM2 interacts with prolyl hydroxylase-3 to further increase PKM2 coactivator function. Together, these promote a feed-forward mechanism that drives the reprogramming of cancer cells to glycolytic metabolism. Rey and colleagues investigated methods of manipulating HIF-1 activation to optimize the homing, retention, survival, and tissue-sparing effects of bone marrow-derived angiogenic cells (BMDACs) in a mouse model of limb ischemic injury. This model includes local injection of an HIF-1α-encoding recombinant adenovirus.1 They observed that pretreatment of BMDACs from young and old mice with dimethyloxalylglycine, which potentiates HIF-1 activation and induces the Warburg effect, allows these cells to survive longer than untreated BMDACs in low oxygen and low pH states and to significantly reduce ischemic tissue damage and motor impairment caused by femoral artery ligation.
The observations in these two papers emphasize the value of understanding HIF-1 activity in normal physiology and disease states. The complex PKM2 interactions delineated by Luo et al. reveal potential therapeutic targets against cancer cells that have co-opted the HIF pathway to utilize glucose for basal metabolism and tumors growing in hypoxic conditions. The outcomes observed by Rey et al. in a murine model that combines local HIF-1α gene therapy with BMDACs primed for glycolytic metabolism by HIF-1 activation raise the hope that similar manipulations might be useful for cell-based therapies in patients with severe tissue ischemia. These findings also have broader relevance, as it is now recognized that many HIF-1-mediated regulatory pathways modulate homeostasis in tissues with low-oxygen microenvironments, such as the bone marrow.2
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- Rey S, Lee K, Wang CJ, et al. Synergistic effect of HIF-1α gene therapy and HIF-1-activated bone marrow-derived angiogenic cells in a mouse model of limb ischemia. Proc Natl Acad Sci USA. 2009;106:20399-20404.
- Rehn M, Olsson A, Reckzeh K, et al. Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche. Blood. 2011. [Epub ahead of print].