Exosomal LOC85009 inhibits docetaxel resistance in lung adenocarcinoma through regulating ATG5-induced autophagy

Drug Resist Updat. 2023 Mar:67:100915. doi: 10.1016/j.drup.2022.100915. Epub 2022 Dec 26.

Authors

Zhengyuan Yu¹, Hailin Tang², Shaomu Chen³, Yufeng Xie³, Liyan Shi¹, Shuhua Xia¹, Min Jiang⁴, Jiaoyang Li⁵, Dongqin Chen⁶

Affiliations

¹ Department of Medical Oncology, The First Affiliated Hospital of Soochow University, No.188 Shizi Street, Gusu District, Suzhou 215006, Jiangsu, China.
² Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510062, Guangdong, China.
³ Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, No.188 Shizi Street, Gusu District, Suzhou 215006, Jiangsu, China.
⁴ Department of Medical Oncology, The First Affiliated Hospital of Soochow University, No.188 Shizi Street, Gusu District, Suzhou 215006, Jiangsu, China. Electronic address: jiangmin1023@suda.edu.cn.
⁵ Department of Ultrasound, Guangdong Provincial People's Hospital, (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 519041, Guangdong, China. Electronic address: xianjiao864335177@163.com.
⁶ Department of Medical Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pujian Road, Pudong New District, Shanghai, 200127, China; Department of Oncology, Nantong City No. 1 People's Hospital and Second Affiliated Hospital of Nantong University, No. 666, Shengli Road, Nantong 226000, Jiangsu Province, China. Electronic address: drdqchen@163.com.

PMID: 36641841
DOI: 10.1016/j.drup.2022.100915

Abstract

Aims: This study aims at investigating the role of a neighbor long non-coding RNA (lncRNA) of HDAC4 (LOC85009) in docetaxel (DTX) resistance of lung adenocarcinoma (LUAD).

Methods: RT-qPCR was used to analyze LOC85009 expression in DTX-resistant LUAD cells. In vitro and in vivo experiments were applied to detect the influence of LOC85009 on LUAD cell growth and xenograft tumor growth. DNA pull down assay, RNA pull down assay, ChIP assay, CoIP assay and RIP assay were performed to identify the direct interactions between factors.

Results: LOC85009 was lowly-expressed in DTX-resistant LUAD cells. Functionally, LOC85009 overexpression inhibited DTX resistance and cell proliferation but triggered cell apoptosis. Moreover, we identified that LOC85009 was transferred from LUAD cells to DTX-resistant LUAD cells via exosomes. Exosomal LOC85009 inhibited DTX resistance, proliferation and autophagy while induced apoptosis in DTX-resistant cells. Additionally, we found that LOC85009 sequestered ubiquitin-specific proteinase 5 (USP5) to destabilize upstream transcription factor 1 (USF1) protein, thereby inactivating ATG5 transcription.

Conclusions: Exosomal LOC85009 inhibits DTX resistance through regulation of ATG5-induced autophagy via USP5/USF1 axis, suggesting that LOC85009 might be a potential target to reverse DTX resistance in the treatment of LUAD.

Keywords: ATG5; Docetaxel; LOC85009; Lung adenocarcinoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma* / drug therapy
Adenocarcinoma* / genetics
Adenocarcinoma* / metabolism
Autophagy / genetics
Autophagy-Related Protein 5 / genetics
Autophagy-Related Protein 5 / metabolism
Autophagy-Related Protein 5 / therapeutic use
Cell Line, Tumor
Cell Proliferation
Docetaxel* / pharmacology
Docetaxel* / therapeutic use
Drug Resistance, Neoplasm* / genetics
Gene Expression Regulation, Neoplastic
Humans
Lung / metabolism
Lung / pathology
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
MicroRNAs* / genetics

Substances

ATG5 protein, human
Autophagy-Related Protein 5
Docetaxel
MicroRNAs
HDAC4 protein, human