55 research outputs found
Hypoxia Triggers Major Metabolic Changes in AML Cells without Altering Indomethacin-Induced TCA Cycle Deregulation
AKR1C enzymes sustain therapy resistance in paediatric T-ALL
BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (TALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy
Environmental sensing and response genes in cnidaria : the chemical defensome in the sea anemone Nematostella vectensis
Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Cell Biology and Toxicology 24 (2008): 483-502, doi:10.1007/s10565-008-9107-5.The starlet sea anemone Nematostella vectensis has been recently established as a
new model system for the study of the evolution of developmental processes, as cnidaria
occupy a key evolutionary position at the base of the bilateria. Cnidaria play important
roles in estuarine and reef communities, but are exposed to many environmental stressors.
Here I describe the genetic components of a ‘chemical defensome’ in the genome of
N. vectensis, and review cnidarian molecular toxicology. Gene families that defend
against chemical stressors and the transcription factors that regulate these genes have
been termed a ‘chemical defensome,’ and include the cytochromes P450 and other
oxidases, various conjugating enyzymes, the ATP-dependent efflux transporters,
oxidative detoxification proteins, as well as various transcription factors. These genes
account for about 1% (266/27200) of the predicted genes in the sea anemone genome,
similar to the proportion observed in tunicates and humans, but lower than that observed
in sea urchins. While there are comparable numbers of stress-response genes, the stress
sensor genes appear to be reduced in N. vectensis relative to many model protostomes
and deuterostomes. Cnidarian toxicology is understudied, especially given the important
ecological roles of many cnidarian species. New genomic resources should stimulate the
study of chemical stress sensing and response mechanisms in cnidaria, and allow us to
further illuminate the evolution of chemical defense gene networks.WHOI Ocean Life Institute and NIH R01-ES01591
Benzo(a)pyrene affects proliferation with reference to metabolic genes and ROS/HIF-1α/HO-1 signaling in A549 and MCF-7 cancer cells
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