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Inhibition of Skp2 sensitizes lung cancer cells to paclitaxel

Authors Huang T, Yang L, Wang G, Ding G, Peng B, Wen Y, Wang Z

Received 26 October 2016

Accepted for publication 14 December 2016

Published 18 January 2017 Volume 2017:10 Pages 439—446

DOI https://doi.org/10.2147/OTT.S125789

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ashok Kumar Pandurangan

Peer reviewer comments 3

Editor who approved publication: Dr Carlos Vigil Gonzales

Tonghai Huang, Lin Yang, Guangsuo Wang, Guanggui Ding, Bin Peng, Yuxin Wen, Zheng Wang

Department of Thoracic Surgery, Shenzhen People’s Hospital, Shenzhen, Guangdong Province, People’s Republic of China

Abstract: S-phase kinase-associated protein 2 (Skp2) is an E3 ubiquitin ligase and plays an important role in the control of cell cycle progression. Skp2 is upregulated in several cancers, including lung cancers, but the role of Skp2 in the tumorigenesis and anticancer drug resistance in human lung cancer remains to be determined. We report here that Skp2 positively regulated mitotic arrest deficient 2 (MAD2) expression and that inhibition of Skp2 sensitizes human lung cancer cells to paclitaxel. Knockdown of Skp2 by small interfering RNA (siRNA) decreased Mad2 messenger RNA (mRNA) and protein levels in A549 and NCI-H1975 cells, accompanied with upregulation of p27 but decrease of the phosphorylation of retinoblastoma (Rb). In contrast, ectopic overexpression of Skp2 increased Mad2 mRNA and protein levels and phosphorylation of Rb, while it decreased p27. Pharmacological inhibition of CDK1/2 by flavopiridol or E2F1 with HLM006474 led to downregulation of Mad2 expression and prevented the increase of Mad2 expression by Skp2. Most importantly, pharmacological inhibition of Skp2 sensitized A549 and NCI-H1299 cells to paclitaxel. Our results demonstrated that SKP2 positively regulates the gene expression of MAD2 through p27-CDKs-E2F1 signaling pathway and that inhibition of Skp2 sensitizes A549 and NCI-H1299 cells to paclitaxel, suggesting that small molecule inhibitors of Skp2 are potential agents for the treatment of lung cancer with upregulation of Skp2.

Keywords: SKP2, MAD2, spindle assembly checkpoint, lung cancer, paclitaxel

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