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Inhibition of CRM1 activity sensitizes endometrial and ovarian cell lines to TRAIL-induced cell death

Overview of attention for article published in Cell Communication and Signaling, July 2018
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Title
Inhibition of CRM1 activity sensitizes endometrial and ovarian cell lines to TRAIL-induced cell death
Published in
Cell Communication and Signaling, July 2018
DOI 10.1186/s12964-018-0252-z
Pubmed ID
Authors

François Fabi, Pascal Adam, Keven Vincent, Françis Demontigny, Sophie Parent, France-Hélène Joncas, Eric Asselin

Abstract

CRM1 enrichment has been shown to be indicative of invasive as well as chemoresistant tumors. On the other hand, TRAIL, a powerful and specific anti-tumoral agent, has yet to be used effectively to treat gynecological tumors in patients. In the present study, we examined if CRM1, a nuclear exporter capable of mediating protein transport, could be a relevant target to restore chemosensitivity in chemoresistant cells. We thus explored the hypothesis that CRM1-driven nuclear exclusion of tumor suppressors could lead to chemoresistance and that CRM1 inhibitors could present a novel therapeutic approach, allowing sensitization to chemotherapeutic agents. Ovarian cancer cell lines, as well as endometrial cancer cell lines, were treated with leptomycin B (LMB), cisplatin and TRAIL, either singly or in combination, in order to induce apoptosis. Western blot and flow cytometry analysis were used to quantify caspases activation and apoptosis induction. Immunofluorescence was used to determine nuclear localization of p53. Colony formation assays were performed to determine therapeutic effectiveness; p53 siRNA were used to establish p53 role in sensitization. Additional information from GEO database and Prognoscan allowed us to contextualise the obtained results. Finally, qRT-PCR was performed to measure apoptotic regulators expression. TRAIL and LMB combination therapy lead to cleavage of caspase-3 as well as the appearance of cleaved-PARP, and thus, apoptosis. Further experiments suggested that sensitization was achieved through the synergistic downregulation of multiple inhibitor of apoptosis, as well as the activation of apoptotic pathways. p53 was enriched in the nucleus following LMB treatments, but did not seem to be required for sensitization; additional experiments suggested that p53 opposed the apoptotic effects of LMB and TRAIL. Results obtained from public data repositories suggested that CRM1 was a driver of chemoresistance and poor prognostic; DR5, on the other hand, acted as as a marker of positive prognostic. Taken together, our results suggest that the use of CRM1 inhibitors, in combination to chemotherapeutic compounds, could be highly effective in the treatment of gynecological malignancies.

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The data shown below were collected from the profiles of 2 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 15 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 15 100%

Demographic breakdown

Readers by professional status Count As %
Other 1 7%
Student > Bachelor 1 7%
Student > Ph. D. Student 1 7%
Student > Master 1 7%
Researcher 1 7%
Other 1 7%
Unknown 9 60%
Readers by discipline Count As %
Medicine and Dentistry 2 13%
Agricultural and Biological Sciences 1 7%
Chemistry 1 7%
Social Sciences 1 7%
Unknown 10 67%
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 06 July 2018.
All research outputs
#17,982,872
of 23,094,276 outputs
Outputs from Cell Communication and Signaling
#640
of 1,020 outputs
Outputs of similar age
#237,075
of 328,026 outputs
Outputs of similar age from Cell Communication and Signaling
#11
of 25 outputs
Altmetric has tracked 23,094,276 research outputs across all sources so far. This one is in the 19th percentile – i.e., 19% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,020 research outputs from this source. They receive a mean Attention Score of 4.0. This one is in the 22nd percentile – i.e., 22% of its peers scored the same or lower than it.
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 328,026 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 22nd percentile – i.e., 22% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 25 others from the same source and published within six weeks on either side of this one. This one is in the 40th percentile – i.e., 40% of its contemporaries scored the same or lower than it.