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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2016 | Research

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

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

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2016

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

Thus, LCL161 could be a useful agent for the treatment of NSCLC in combination with paclitaxel.

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Title: LCL161 increases paclitaxel-induced apoptosis by degrading cIAP1 and cIAP2 in NSCLC
Authors: Chengcheng Yang
Huangzhen Wang
Boxiang Zhang
Yimeng Chen
Yamin Zhang
Xin Sun
Guodong Xiao
Kejun Nan
Hong Ren
Sida Qin
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2016
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-016-0435-7

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Abstract

Background

Methods

Results

Conclusion

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