Insight into Hypoxia Tolerance in Cowpea Bruchid: Metabolic Repression and Heat Shock Protein Regulation via Hypoxia-Inducible Factor 1

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Identification of heat shock protein 60 as the regulator of the hypoxia-inducible factor subunit HIF-1α

Pure and Applied Chemistry ◽

10.1351/pac-con-11-11-03 ◽

2012 ◽

Vol 84 (11) ◽

pp. 2325-2337 ◽

Cited By ~ 9

Author(s):

Hyun Seung Ban ◽

Kazuki Shimizu ◽

Hidemitsu Minegishi ◽

Hiroyuki Nakamura

Keyword(s):

Growth Factor ◽

Heat Shock ◽

Heat Shock Protein ◽

Click Reaction ◽

Photoaffinity Labeling ◽

Hypoxia Inducible Factor ◽

Fluorescent Imaging ◽

Target Protein ◽

Heat Shock Protein 60 ◽

Pathological Angiogenesis

The hypoxia-inducible factor (HIF) takes part in transcriptional activation of hypoxia-responsive genes such as vascular endothelial growth factor (VEGF), insulin-like growth factor, and inducible nitric oxide synthase. Since VEGF plays an important role in pathological angiogenesis such as tumor growth and ischemic diseases, the inhibition of VEGF inducer HIF is an attractive approach for the inhibition of pathological angiogenesis. Recently, we have reported that the introduction of boronic acid and a carborane moiety into phenoxyacetanilide induced a potent inhibitory effect on HIF-1α activation under hypoxic conditions. In the present study, to clarify the mechanism of action of carboranylphenoxyacetanilide GN26361 against HIF inhibition, we designed and synthesized molecular probes of GN26361 substituted with benzophenone to induce covalent binding with the target protein by UV (photoaffinity labeling) and an acetylenic moiety to conjugate with the green-fluorescent Alexa Fluor 488-azide by click reaction. In-gel fluorescent imaging of target protein bound with the probe was identified as heat shock protein 60 (HSP60). Moreover, direct binding in gel fluorescent imaging was observed by photoaffinity labeling and click reaction of the probe with recombinant HSP60. These results indicate that HSP60 is the target protein of GN26361 and might be a new molecular target for HIF inhibition.

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