Contributions
Abstract: E904
Type: Eposter Presentation
Background
Aims
The aim of this project is to explore cellular and molecular alterations induced by Kevetrin, focusing on its role in the p53 pathway.
Methods
Results
Our data indicate that Kevetrin exposure induces cell growth arrest, a great drop of mitochondrial membrane potential and a remarkable increment of Caspase-3 cleaved form, features that contribute to apoptotic cell death in the two cell lines. Cellular changes can be associated with a dose and time-dependent effect in the TP53 mutated cell line (KASUMI-1) but not in the wild type one (MOLM-13), in which we can observe an activity only after 48 h at the higher concentration. Regarding molecular alterations in KASUMI-1 we found a great p53 down-regulation, probably due to Hsp90 reduction, resulting in a less marked formation of the Hsp90-p53 oncogenic complex. We also found a down-regulated p53 active form (Ser15), a reduced expression of p53 targets, p21 and PUMA, and a down-regulation of SIRT-3, that cannot exert its inhibitory activity on p53. The MOLM-13 cell line showed a great p53 reduction, probably related to SIRT-3 up-regulation and Hsp90 down-regulation. Regarding p53 active form, we noticed slight variations in protein expression, suggesting a physiological response of the protein to cellular damage. In accordance with p53 activity, we observed a great up-regulation of p21, probably associated with a drug resistance mechanism; in contrast, PUMA protein was highly down-regulated, suggesting a p53-independent mechanism of action or a feedback regulation of the apoptotic process, after Caspase-3 activation (Figure). In order to better understand drug’s mechanism of action we are performing gene expression profiling after 48 h of treatment with Kevetrin 60 μg/ml.
Conclusion
Session topic: 3. Acute myeloid leukemia - Biology
Abstract: E904
Type: Eposter Presentation
Background
Aims
The aim of this project is to explore cellular and molecular alterations induced by Kevetrin, focusing on its role in the p53 pathway.
Methods
Results
Our data indicate that Kevetrin exposure induces cell growth arrest, a great drop of mitochondrial membrane potential and a remarkable increment of Caspase-3 cleaved form, features that contribute to apoptotic cell death in the two cell lines. Cellular changes can be associated with a dose and time-dependent effect in the TP53 mutated cell line (KASUMI-1) but not in the wild type one (MOLM-13), in which we can observe an activity only after 48 h at the higher concentration. Regarding molecular alterations in KASUMI-1 we found a great p53 down-regulation, probably due to Hsp90 reduction, resulting in a less marked formation of the Hsp90-p53 oncogenic complex. We also found a down-regulated p53 active form (Ser15), a reduced expression of p53 targets, p21 and PUMA, and a down-regulation of SIRT-3, that cannot exert its inhibitory activity on p53. The MOLM-13 cell line showed a great p53 reduction, probably related to SIRT-3 up-regulation and Hsp90 down-regulation. Regarding p53 active form, we noticed slight variations in protein expression, suggesting a physiological response of the protein to cellular damage. In accordance with p53 activity, we observed a great up-regulation of p21, probably associated with a drug resistance mechanism; in contrast, PUMA protein was highly down-regulated, suggesting a p53-independent mechanism of action or a feedback regulation of the apoptotic process, after Caspase-3 activation (Figure). In order to better understand drug’s mechanism of action we are performing gene expression profiling after 48 h of treatment with Kevetrin 60 μg/ml.
Conclusion
Session topic: 3. Acute myeloid leukemia - Biology
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