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Molecular mechanism leading to SAHA-induced autophagy in tumor cells: evidence for a p53-dependent pathway

Overview of attention for article published in Cancer Cell International, September 2016
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Title
Molecular mechanism leading to SAHA-induced autophagy in tumor cells: evidence for a p53-dependent pathway
Published in
Cancer Cell International, September 2016
DOI 10.1186/s12935-016-0343-0
Pubmed ID
Authors

Leopold F. Fröhlich, Maria Mrakovcic, Claudia Smole, Kurt Zatloukal

Abstract

Recent studies indicated that histone deacetylase inhibitors (HDACi), a class of anticancer agents, are in addition to their ability of apoptosis induction also capable of provoking autophagy. Promoted by the treatment of malignant uterine sarcoma cells with the HDACi suberoylanilide hydroxamic acid (SAHA), we previously demonstrated predominant dose-dependent activation of autophagy in ESS-1 cells, but prevalent induction of apoptosis in MES-SA cells. In order to extend our previous studies, SAHA-treated ESS-1 and MES-SA cells were monitored for protein expression to reveal differences in known markers of apoptosis explaining the different cytotoxic responses. Further analysis of the identified candidate protein included cell rescue experiments by gene transfer followed by subsequent screening of cells for induction of apoptosis and autophagy by immunoblotting, caspase activity as well as LC3 and MDC/PI staining. LDH release assays were performed to assess the amount of cell-mediated cytotoxicity. In our search for responsible autophagic regulatory genes upstream of mammalian target of rapamycin (mTOR), we now discovered that, in contrast to MES-SA cells, a TP53-637C>T nonsense mutation located in the transactivating domain of the oncogenic suppressor p53 causes loss of its protein and consequently reduced PUMA induction in ESS-1 cells. Upon re-introduction of wild-type TP53, SAHA-treated ESS-1 cells underwent immediate apoptotic cell death as supported by upregulation of PUMA and caspase-9 as well as by activation of caspases-3 and -7 and PARP-1 cleavage. Concurrent downregulation of autophagy was noticed by upregulated mTor and phospho-mTOR expression as well as monitoring autophagosome formation employing LC3 and MDC staining. Previously, cytoplasmic master regulatory activities of the oncogenic suppressor p53 in inhibiting autophagy and triggering apoptosis were unravelled. Accordingly, p53-deficiency could explain both, the previously documented apoptosis resistance and prevailing SAHA-induced autophagy in ESS-1 cells. Using MES-SA cells with RNAi-silenced p53 expression and several p53-deficient tumor cell lines undergoing SAHA-induced autophagy, we could generally validate our finding suggesting an inhibitory role for p53 in the autophagic pathway in response to SAHA treatment. Conclusively, these results could identify cytoplasmic p53 protein as a molecular switch that directly mediates the cytotoxic response of SAHA and thus open new therapeutic avenues.

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Mendeley readers

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The data shown below were compiled from readership statistics for 19 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 19 100%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 4 21%
Researcher 3 16%
Student > Ph. D. Student 2 11%
Student > Doctoral Student 1 5%
Other 1 5%
Other 3 16%
Unknown 5 26%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 6 32%
Agricultural and Biological Sciences 3 16%
Medicine and Dentistry 3 16%
Neuroscience 1 5%
Unknown 6 32%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 28 October 2016.
All research outputs
#18,469,995
of 22,886,568 outputs
Outputs from Cancer Cell International
#1,090
of 1,804 outputs
Outputs of similar age
#255,843
of 334,695 outputs
Outputs of similar age from Cancer Cell International
#9
of 12 outputs
Altmetric has tracked 22,886,568 research outputs across all sources so far. This one is in the 11th percentile – i.e., 11% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,804 research outputs from this source. They receive a mean Attention Score of 3.8. This one is in the 24th percentile – i.e., 24% of its peers scored the same or lower than it.
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We're also able to compare this research output to 12 others from the same source and published within six weeks on either side of this one. This one is in the 16th percentile – i.e., 16% of its contemporaries scored the same or lower than it.