Phosphatase Regulation of HIF-1α Activity in Glioblastoma Multiforme (GBM)
Zones of the GBM tumor microenvironment.
HIF expression is predominantly observed
in the psudopalisading regions
surrounding the necrotic core.
Approximately 14,000 patients are diagnosed with glioblastoma multiforme (GBM) in the United States annually, and current standard-of-care therapy including surgical resection followed by radiation and adjunctive temozolomide treatment typically results in a median survival of only 12-15 months from diagnosis. The high level of genotypic aberration encompassing these lesions manifests in extreme phenotypic heterogeneity comprised of pseudopalisading regions demarcated by varying levels of nutrient deprivation and hypoxia. Interestingly, many of the molecular defects associated with glioma result in increased signaling activity of the hypoxia inducible factor-1α (HIF-1α), a transcription factor linked elsewhere to tumor cell growth, angiogenesis, invasion, and glycolytic shift.
A hallmark of cancer cells is their ability to survive in the hypoxic microenvironment through metabolic reprogramming, favoring glycolysis over oxidative phosphorylation to support their aggressive energy and macromolecule requirements in a phenomenon known as the
Warburg effect. HIF-1α heterodimerizes with its nuclear co-activator HIF-1β to activate a family of genes associated with promoting glycolysis including glucose transporters and enzymes involved in the glycolytic pathway, as well as metabolite transporters and enzymes involved in regulating cellular pH under conditions favoring acidosis. Thus, combination of the hypoxic tumor microenvironment and genetic aberrations common to GBM synergize to increase HIF-1α protein levels far in excess of those observed in normal tissue.
Mitogen-activated protein kinase phosphatase-1 (MKP-1/DUSP1) is a ubiquitously expressed phosphatase and its enforced expression enhances the accumulation of transcriptionally inactive hypo-phosphorylated forms of HIF-1α. While MKP-1 expression appears elevated in brain, breast, lung, ovarian, levels are reduced in others including pancreatic, prostate, colon, and bladder. MKP-1 overexpression has been suggested as a potential source of chemoresistance given its effects on the MAPK c-Jun N-terminal kinase pathway, however, MKP-1 induction following oxidative stress induces a pro-apoptotic effect by interrupting MAPK pro-survival signaling, and drug induction in GBM cells has shown anti-tumor activity by decreasing invasion and migration.
To better understand the role of MKP-1 in glioblastoma multiforme, we are investigating the relationship between MKP/DUSP expression and HIF-1 dependent signaling in both cultured lines and primary tumor resects. Our data indicate that DUSP activity is altered in GBM, is regulated by several anti-cancer treatments, and may exhibit novel anti-tumorigenic properties in our models. Progress in this area could have important implications regarding the development of novel therapeutic strategies for this fatal disorder.
Necrotic focus surrounded by the feature
of "pseudopalisading" cells
relatively unique to malignant gliomas.
Methods of treatment and screening assays for hif-1alpha regulation (US 20120251629 A1)
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