Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor hypoxia in a solid tumor mass has long been recognized as a cause of resistance to current cancer therapies, and has also been suggested to be a potent driving force towards malignancy. Recent progress in the understanding of the molecular mechanism of the tumor response to hypoxia has increased attention on targeting hypoxia for cancer therapy. We have generated a hypoxia-targeting fusion protein, TOP3, which is composed of a protein transduction domain (PTD) of HIV TAT, an oxygen-dependent degradation domain (ODD) of HIF-1 alpha, and procaspase-3. Here, we examine the effects of TOP3 in a rat ascites model. First, we clarified that the fluid in ascites from MM1 cells, which are derivatives of AH130 rat ascites hepatoma cells, was highly hypoxic. In vitro, MM1 cells retained protein degradation machinery through the ODD domain, and TOP3 effectively impaired MM1 cell growth in culture under hypoxic conditions by inducing apoptosis. Intraperitoneal administration of TOP3 prolonged the life span of rats bearing a significant amount of malignant ascites, and 60% of the treated animals were cured without recurrence of ascites. Thus, TOP3 had a dramatic effect on malignant ascites and, hence, we propose that rodent malignant ascites is an appropriate platform for testing hypoxia-targeted drugs.
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PMID:Targeting hypoxic cancer cells with a protein prodrug is effective in experimental malignant ascites. 1528 74

Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a major regulator of adaptation to hypoxia and is implicated in the malignant progression of cancers. Here, we studied whether hypoxia and HIF-1 expression contribute to the development of bone metastases using a well-characterized animal model of bone metastasis in MDA-MB-231 human breast cancer cells. To study the role of hypoxia in bone metastases, we tested the effects of the fusion protein (TOP3), the oxygen-dependent degradation domain of HIF-1alpha fused with HIV-TAT, and procaspase-3. TOP3 selectively induced apoptosis in hypoxic tumor cells in vitro and significantly reduced bone metastases in vivo. We next examined the role of HIF-1 in bone metastases by establishing MDA-MB-231 cells overexpressing constitutively active or dominant-negative HIF-1alpha (MDA/CA-HIF or MDA/DN-HIF, respectively). Bone metastases of MDA/CA-HIF were significantly increased with elevated number of CD31-positive blood vessels. In contrast, bone metastases were significantly reduced in MDA/DN-HIF. Because the progression of osteolytic bone metastases is due in part to the imbalance between bone formation and bone resorption, we examined the effects of hypoxia and HIF-1 on the differentiation of osteoblasts and osteoclasts. Hypoxia and CA-HIF overexpression markedly inhibited osteoblastic differentiation, whereas hypoxia increased osteoclast-like cell formation. In conclusion, these results suggest that tumor-associated hypoxia and HIF-1 expression promote the progression of bone metastases in breast cancer. Our results also suggest that hypoxia and HIF-1 lead to the development of osteolytic bone metastases by suppressing osteoblast differentiation and promoting osteoclastogenesis.
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PMID:Hypoxia and hypoxia-inducible factor-1 expression enhance osteolytic bone metastases of breast cancer. 1748 26