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3-BrPA eliminates human bladder cancer cells with highly oncogenic signatures via engagement of specific death programs and perturbation of multiple signaling and metabolic determinants

Overview of attention for article published in Molecular Cancer, July 2015
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  • In the top 25% of all research outputs scored by Altmetric
  • Good Attention Score compared to outputs of the same age (75th percentile)
  • High Attention Score compared to outputs of the same age and source (93rd percentile)

Mentioned by

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6 tweeters
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1 Google+ user

Citations

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19 Dimensions

Readers on

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31 Mendeley
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Title
3-BrPA eliminates human bladder cancer cells with highly oncogenic signatures via engagement of specific death programs and perturbation of multiple signaling and metabolic determinants
Published in
Molecular Cancer, July 2015
DOI 10.1186/s12943-015-0399-9
Pubmed ID
Authors

Eumorphia G. Konstantakou, Gerassimos E. Voutsinas, Athanassios D. Velentzas, Aggeliki-Stefania Basogianni, Efthimios Paronis, Evangelos Balafas, Nikolaos Kostomitsopoulos, Konstantinos N. Syrigos, Ema Anastasiadou, Dimitrios J. Stravopodis

Abstract

Urinary bladder cancer is one of the most fatal and expensive diseases of industrialized world. Despite the strenuous efforts, no seminal advances have been achieved for its clinical management. Given the importance of metabolic reprogramming in cancer cell survival and growth, we have herein employed 3-BrPA, a halogenated derivative of pyruvate and historically considered inhibitor of glycolysis, to eliminate bladder cancer cells with highly oncogenic molecular signatures. Bladder cancer cells were exposed to 3-BrPA in the absence or presence of several specific inhibitors. Cell viability was determined by MTT and flow-cytometry assays; cell death, signaling activity and metabolic integrity by Western blotting and immunofluorescence; mutant-gene profiling by DNA sequencing; and gene expression by RT-sqPCR. 3-BrPA could activate dose-dependent apoptosis (type 1 PCD) and regulated necrosis (type 3 PCD) of T24 (grade III; H-Ras(G12V); p53(ΔY126)), but not RT4 (grade I), cells, with PARP, MLKL, Drp1 and Nec-7-targeted components critically orchestrating necrotic death. However, similarly to RIPK1 and CypD, p53 presented with non-essential contribution to 3-BrPA-induced cellular collapse, while reactivation of mutant p53 with PRIMA-1 resulted in strong synergism of the two agents. Given the reduced expression of MPC components (likely imposing mitochondrial dysfunction) in T24 cells, the suppression of constitutive autophagy (required by cells carrying oncogenic Ras; also, type 2 PCD) and derangement of glucose-homeostasis determinants by 3-BrPA critically contribute to drug-directed depletion of ATP cellular stores. This bioenergetic crisis is translated to severe dysregulation of Akt/FoxO/GSK-3, mTOR/S6, AMPK and MAPK (p44/42, p38 and SAPK/JNK) signaling pathways in 3-BrPA-treated T24 cells. Sensitivity to 3-BrPA (and tolerance to glucose deprivation) does not rely on B-Raf(V600E) or K-Ras(G13D) mutant oncogenic proteins, but partly depends on aberrant signaling activities of Akt, MAPK and AMPK kinases. Interestingly, MCT1- and macropinocytosis-mediated influx of 3-BrPA in T24 represents the principal mechanism that regulates cellular responsiveness to the drug. Besides its capacity to affect transcription in gene-dependent manner, 3-BrPA can also induce GLUT4-specific splicing silencing in both sensitive and resistant cells, thus dictating alternative routes of drug trafficking. Altogether, it seems that 3-BrPA represents a promising agent for bladder cancer targeted therapy.

Twitter Demographics

The data shown below were collected from the profiles of 6 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 31 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 31 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 7 23%
Student > Ph. D. Student 6 19%
Student > Master 5 16%
Other 2 6%
Student > Postgraduate 2 6%
Other 5 16%
Unknown 4 13%
Readers by discipline Count As %
Agricultural and Biological Sciences 8 26%
Biochemistry, Genetics and Molecular Biology 7 23%
Medicine and Dentistry 5 16%
Immunology and Microbiology 2 6%
Psychology 2 6%
Other 3 10%
Unknown 4 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 5. 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 25 July 2015.
All research outputs
#2,150,515
of 9,722,866 outputs
Outputs from Molecular Cancer
#124
of 949 outputs
Outputs of similar age
#57,880
of 235,496 outputs
Outputs of similar age from Molecular Cancer
#3
of 48 outputs
Altmetric has tracked 9,722,866 research outputs across all sources so far. Compared to these this one has done well and is in the 77th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 949 research outputs from this source. They receive a mean Attention Score of 3.3. This one has done well, scoring higher than 86% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 235,496 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 75% of its contemporaries.
We're also able to compare this research output to 48 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 93% of its contemporaries.