A small compound spindlactone A sensitizes human endometrial cancer cells to TRAIL-induced apoptosis via the inhibition of NAD(P)H dehydrogenase quinone 1
Authors Zhao XZ, Wu XH
Received 16 February 2018
Accepted for publication 12 May 2018
Published 21 June 2018 Volume 2018:11 Pages 3609—3617
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Cristina Weinberg
Peer reviewer comments 2
Editor who approved publication: Dr Yao Dai
Xiang-Zhai Zhao,1 Xiao-Hua Wu2,3
1Department of Gynecology and Obstetrics, The Third Hospital of Hebei Medical University, Hebei 050051, People’s Republic of China; 2Department of Gynecology and Obstetrics, Hebei Medical University, Hebei 050000, People’s Republic of China; 3Department of Gynecology and Obstetrics, Shijiazhuang Obstetrics and Gynecology Hospital, Hebei Medical University, Hebei 050000, People’s Republic of China
Introduction: Spindlactone A (SPL-A) is a novel small molecule inhibitor of TACC3 that selectively inhibits the nucleation of centrosome microtubules and induces mitotic arrest in ovarian cancer cells. SPL-A is derived from dicoumarol which inhibits the activity of NAD(P)H dehydrogenase quinone oxidoreductase 1 (NQO1). This study aimed to investigate the mechanism by which SPL-A enhances TRAIL-induced apoptosis in endometrial carcinoma cells.
Materials and methods: Endometrial carcinoma cells were treated with SPL-A and/or TRAIL, and the apoptosis and protein expression in the treated cells were examined.
Results: Combined treatment with SPL-A and TRAIL significantly induced apoptosis in various human endometrial carcinoma cells, but not in normal human endometrial stromal cells and endometrial epithelial cells. Notably, both NQO1 inhibitor ES936 and NQO1 siRNA enhanced TRAIL-induced apoptosis of endometrial carcinoma cells. Furthermore, SPL-A downregulated the expression of c-FLIP, Bcl-2, Bcl-xl, and Mcl-1, while increasing p53 expression.
Conclusion: In particular, luciferase assay showed that SPL-A inhibited Bcl-2 promoter activity, and p53 inhibitor PFT-α could reverse the effect of SPL-A on Bcl-2 expression. Moreover, Bcl-2 overexpression inhibited the apoptosis induced by SPL-A and TRAIL. Taken together, our results suggest that SPL-A sensitizes endometrial cancer cells to TRAIL-induced apoptosis via the regulation of apoptosis-related proteins and the inhibition of NQO1 activity.
Keywords: dicoumarol derivative, SPL-A, endometrial carcinoma, TRAIL, Bcl-2, apoptosis, NQO1
Corrigendum for this paper has been published
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]