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LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC

Overview of attention for article published in Journal of Experimental & Clinical Cancer Research, September 2016
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  • High Attention Score compared to outputs of the same age and source (88th percentile)

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Title
LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC
Published in
Journal of Experimental & Clinical Cancer Research, September 2016
DOI 10.1186/s13046-016-0435-7
Pubmed ID
Authors

Chengcheng Yang, Huangzhen Wang, Boxiang Zhang, Yimeng Chen, Yamin Zhang, Xin Sun, Guodong Xiao, Kejun Nan, Hong Ren, Sida Qin

Abstract

LCL161, a novel Smac mimetic, is known to have anti-tumor activity and improve chemosensitivity in various cancers. However, the function and mechanisms of the combination of LCL161 and paclitaxel in non-small cell lung cancer (NSCLC) remain unknown. Cellular inhibitor of apoptotic protein 1 and 2 (cIAP1&2) expression in NSCLC tissues and adjacent non-tumor tissues were assessed by immunohistochemistry. The correlations between cIAP1&2 expression and clinicopathological characteristics, prognosis were analyzed. Cell viability and apoptosis were measured by MTT assays and Flow cytometry. Western blot and co-immunoprecipitation assay were performed to measure the protein expression and interaction in NF-kB pathway. siRNA-mediated gene silencing and caspases activity assays were applied to demonstrate the role and mechanisms of cIAP1&2 and RIP1 in lung cancer cell apoptosis. Mouse xenograft NSCLC models were used in vivo to determine the therapeutic efficacy of LCL161 alone or in combination with paclitaxel. The expression of cIAP1 and cIAP2 in Non-small cell lung cancer (NSCLC) tumors was significantly higher than that in adjacent normal tissues. cIAP1 was highly expressed in patients with late TNM stage NSCLC and a poor prognosis. Positivity for both cIAP1 and cIAP2 was an independent prognostic factor that indicated a poorer prognosis in NSCLC patients. LCL161, an IAP inhibitor, cooperated with paclitaxel to reduce cell viability and induce apoptosis in NSCLC cells. Molecular studies revealed that paclitaxel increased TNFα expression, thereby leading to the recruitment of various factors and the formation of the TRADD-TRAF2-RIP1-cIAP complex. LCL161 degraded cIAP1&2 and released RIP1 from the complex. Subsequently, RIP1 was stabilized and bound to caspase-8 and FADD, thereby forming the caspase-8/RIP1/FADD complex, which activated caspase-8, caspase-3 and ultimately lead to apoptosis. In nude mouse xenograft experiments, the combination of LCL161 and paclitaxel degraded cIAP1,2, activated caspase-3 and inhibited tumor growth with few toxic effects. Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.

Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 34 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 34 100%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 6 18%
Student > Master 6 18%
Researcher 4 12%
Student > Ph. D. Student 4 12%
Student > Doctoral Student 2 6%
Other 4 12%
Unknown 8 24%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 8 24%
Agricultural and Biological Sciences 5 15%
Pharmacology, Toxicology and Pharmaceutical Science 3 9%
Chemistry 3 9%
Medicine and Dentistry 3 9%
Other 4 12%
Unknown 8 24%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 4. 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 22 October 2017.
All research outputs
#7,356,550
of 25,374,917 outputs
Outputs from Journal of Experimental & Clinical Cancer Research
#443
of 2,379 outputs
Outputs of similar age
#104,944
of 330,680 outputs
Outputs of similar age from Journal of Experimental & Clinical Cancer Research
#3
of 26 outputs
Altmetric has tracked 25,374,917 research outputs across all sources so far. This one has received more attention than most of these and is in the 69th percentile.
So far Altmetric has tracked 2,379 research outputs from this source. They receive a mean Attention Score of 4.8. This one has done well, scoring higher than 80% 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 330,680 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 67% of its contemporaries.
We're also able to compare this research output to 26 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 88% of its contemporaries.