Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ARC-111, a small-molecule topoisomerase I inhibitor, is a potent cytotoxic drug against multiple human cancer cell lines under normoxic conditions (Li et al., Cancer Res 2003; 63:8400-8407). In this study, we explore the potential of ARC-111 as a hypoxia-inducible factor-1alpha inhibitor under hypoxic conditions. The transcription factor, hypoxia-inducible factor-1alpha, is an essential regulator of tumorigenesis and an attractive molecular target for cancer therapy. We demonstrate that ARC-111 specifically inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1alpha, but not other short half-life proteins in multiple human cancer cell lines. ARC-111 inhibits hypoxia-inducible factor-1alpha protein synthesis specifically and does not inhibit protein synthesis globally. We demonstrate that inhibition of hypoxia-inducible factor-1alpha accumulation by ARC-111 is independent of proteasomal degradation. In addition, we demonstrate using topoisomerase I-resistant cell lines that topoisomerase I is required for ARC-111-mediated hypoxia-inducible factor-1alpha inhibition. Experiments performed with nocodazole indicate that ARC-111 inhibits hypoxia-inducible factor-1alpha accumulation in a cell-cycle-independent manner. Analysis of AKT and mammalian target of rapamycin phosphorylation reveals that ARC-111 does not exhibit inhibitory effect on the phosphatidylinositol-3-kinase AKT mammalian target of rapamycin signaling pathway. It has been previously shown that topotecan, a topoisomerase I inhibitor, can also modulate hypoxia-induced hypoxia-inducible factor-1alpha accumulation (Rapisarda et al., Cancer Res 2003; 64:1475-1482). In addition to inhibiting hypoxia-induced accumulation of hypoxia-inducible factor-1alpha, ARC-111 exhibits antiproliferative effects against multiple human cancer cell lines. We demonstrate that topoisomerase I is required for the antiproliferative effects of ARC-111. Antiproliferative effects of ARC-111, however, are oxygen-independent, which is distinguishable from inhibition of hypoxia-inducible factor-1alpha accumulation by ARC-111, which is only observed under hypoxia. The results indicate that inhibiting hypoxia-inducible factor-1alpha accumulation and exhibiting antiproliferation of ARC-111 are through distinct mechanisms of action, which reinforce the potential anticancer effect of ARC-111 on hypoxic tumors.
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PMID:ARC-111 inhibits hypoxia-mediated hypoxia-inducible factor-1alpha accumulation. 1735 96

Prescription opioid abuse is a serious public health issue. Recently, we showed that female and male Sprague-Dawley rats acquire conditioned place preference (CPP) to the mu opioid receptor agonist oxycodone. Anatomical analysis of the hippocampus from these rats unveiled sex differences in the opioid system in a way that would support excitation and opiate associative learning processes especially in females. In this study, we examined the expression and protein densities of opioid, plasticity, stress and related kinase and signaling molecules in the hippocampus of female and male rats following oxycodone CPP. Oxycodone CPP females have: a) increases in ARC (activity regulated cytoskeletal-associated protein)-immunoreactivity (ir) in CA3 pyramidal cells; b) decreases in Npy (neuropeptide Y) gene expression in the medial hippocampus but higher numbers of NPY-containing hilar interneurons compared to males; c) increases in Crhr2 (corticotropin releasing factor receptor 2) expression in CA2/3; d) increases in Akt1 (AKT serine/threonine kinase 1) expression in medial hippocampus; and e) decreases in phosphorylated MAPK (mitogen activated protein kinase)-ir in CA1 and dentate gyrus. Oxycodone CPP males have: a) increases in Bdnf (brain derived-neurotrophic factor) expression, which is known to be produced in granule cells, relative to females; b) elevated Mapk1 expression and pMAPK-ir in the dentate hilus which harbors newly generated granule cells; and c) increases in CRHR1-ir in CA3 pyramidal cell soma. These sex-specific changes in plasticity, stress and kinase markers in hippocampal circuitry parallel previously observed sex differences in the opioid system after oxycodone CPP.
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PMID:Sex Differences in Neuroplasticity- and Stress-Related Gene Expression and Protein Levels in the Rat Hippocampus Following Oxycodone Conditioned Place Preference. 3107 14