Article

Cathepsin L induced PC-12 cell apoptosis via activation of B-Myb and regulation of cell cycle proteins

Authors: Xiao Shen1, Yi-fan Zhao1, Shu-qing Xu1,2, Long Wang1, Hui-min Cao1, Ying Cao1, Ying Zhu1, Yan Wang1, Zhong-qin Liang1
1 Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, 215123 Suzhou, China
2 Department of Pharmacy, The First People’s Hospital of Wujiang, 215000 Suzhou, China
Correspondence to: Xiao Shen: yanwang@suda.edu.cn, Yan Wang: yanwang@suda.edu.cn, Zhong-qin Liang: liangzhongqin@suda.edu.cn,
DOI: 10.1038/s41401-019-0286-9
Received: 16 February 2019
Accepted: 4 July 2019
Advance online: 23 August 2019

Abstract

Cathepsin L (CTSL), a cysteine protease, is responsible for the degradation of a variety of proteins. It is known to participate in neuronal apoptosis associated with abnormal cell cycle. However, the mechanisms underlying CTSL-induced cell apoptosis remain largely unclear. We reported here that rotenone caused an activation of CTSL expression in PC-12 cells, while knockdown of CTSL by small interfering RNAs or its inhibitor reduced the rotenone-induced cell cycle arrest and apoptosis. Moreover, elevation of CTSL and increased-apoptosis were accompanied by induction of B-Myb, a crucial cell cycle regulator. We found that B-Myb was increased in rotenone-treated PC-12 cells and knockdown of B-Myb ameliorated rotenone-stimulated cell apoptosis. Further analysis demonstrated that CTSL influenced the expression of B-Myb as suppression of CTSL activity led to a decreased B-Myb expression, whereas overexpression of CTSL resulted in B-Myb induction. Reduction of B-Myb in CTSL-overexpressing cells revealed that regulation of cell cycle-related proteins, including cyclin A and cyclin B1, through CTSL was mediated by the transcription factor B-Myb. In addition, we demonstrated that the B-Myb target, Bim, and its regulator, Egr-1, which was also associated with CTSL closely, were both involved in rotenone-induced apoptosis in PC-12 cells. Our data not only revealed the role of CTSL in rotenone-induced neuronal apoptosis, but also indicated the involvement of B-Myb in CTSL-related cell cycle regulation.
Keywords: Cathepsin L; B-Myb; cyclin B1; cyclin A; cell cycle; apoptosis

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