Cathepsin L-mediated resistance of paclitaxel and cisplatin is mediated by distinct regulatory mechanisms.

Abstract

BACKGROUND:

Cathepsin L (CTSL) is a cysteine protease known to have important roles in regulating cancer cellular resistance to chemotherapy. However mechanism underlying which regulates CTSL-mediated drug resistance remain largely unknown.

METHODS:

We used NSCLC cell lines: A549, A549/TAX (paclitaxel-resistant), A549/DDP (cisplatin-resistant), H460 and PC9 cells, to evaluate CTSL and drug resistance changes. Tumor specimens from 53 patients with NSCLC and Xenograft models was also utilized to explore the regulatory relationship of CTSL, TGF-β, Egr-1 and CREB.

RESULTS:

TGF-β and smad3 were overexpressed only in A549/TAX cells, silencing TGF-β or smad3 in A549/TAX cells decreased the expression of CTSL and enhanced their sensitivity to paclitaxel. Smad3 binds to the Smad-binding-element(SBE) of the CTSL promoter, resulting in increased activity of the CTSL promoter and subsequent CTSL. Egr-1 and CREB were overexpressed only in A549/DDP cells, and silencing Egr-1 or CREB reduced the expression of CTSL and increased cisplatin cytotoxicity. CREB could affect the activity of the CTSL promoter by binding to it. And the potential regulatory factors of CTSL were consistent in vivo and in human lung cancer. These different regulatory mechanisms of CTSL-mediated drug resistance exist in two other NSCLC cell lines.

CONCLUSION:

CTSL-mediated drug resistance to paclitaxel and cisplatin may be modulated by different mechanisms. The results of our study identified different mechanisms regulating CTSL-mediated drug resistance and identified smad3 as a novel regulator of CTSL.

• Authors: Yifan Zhao, Xiao Shen, Ying Zhu, Anqi Wang, Yajie Xiong, Long Wang, Yao Fei, Yan Wang, Wenjuan Wang, Fang Lin, Zhongqin Liang
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 38 Issue 1 Pg. 333 (Aug 01 2019) ISSN: 1756-9966 [Electronic] England
• PMID: 31370861 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• CREB1 protein, human
• Cyclic AMP Response Element-Binding Protein
• EGR1 protein, human
• Early Growth Response Protein 1
• SMAD3 protein, human
• Smad3 Protein
• Cathepsin L
• Paclitaxel
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cathepsin L (genetics, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Early Growth Response Protein 1 (metabolism)
• Genes, Reporter
• Humans
• Male
• Paclitaxel (pharmacology)
• Promoter Regions, Genetic
• Protein Binding
• Smad3 Protein (metabolism)
• Xenograft Model Antitumor Assays