The feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 drives lipophagy to induce cisplatin resistance in epithelial ovarian cancer

Yang Shao; Hui Li; Yong Wu; XianYi Wang; Jiao Meng; ZhiXiang Hu; LingFang Xia; SiYu Cao; WenJuan Tian; YunKui Zhang; Xu Feng; XiaoFan Zhang; YanLi Li; Gong Yang

doi:10.1016/j.canlet.2023.216241

The feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 drives lipophagy to induce cisplatin resistance in epithelial ovarian cancer

Cancer Lett. 2023 Jul 1:565:216241. doi: 10.1016/j.canlet.2023.216241. Epub 2023 May 20.

Authors

Yang Shao¹, Hui Li², Yong Wu³, XianYi Wang⁴, Jiao Meng¹, ZhiXiang Hu⁵, LingFang Xia⁶, SiYu Cao⁶, WenJuan Tian⁶, YunKui Zhang⁷, Xu Feng⁸, XiaoFan Zhang⁹, YanLi Li¹⁰, Gong Yang¹¹

Affiliations

¹ Cancer Institute, Fudan University Shanghai Cancer Center and Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
² Cancer Institute, Fudan University Shanghai Cancer Center and Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
³ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁴ Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, 200444, China.
⁵ Department of Integrative Oncology, Fudan University Shanghai Cancer Center, and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
⁶ Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁷ Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁸ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
⁹ Shanghai Collaborative Innovation Center of Agri-Seeds, Joint Center for Single Cell Biology, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China. Electronic address: zhangxf2021@sjtu.edu.cn.
¹⁰ Lab for Noncoding RNA & Cancer, School of Life Sciences, Shanghai University, Shanghai, 200444, China. Electronic address: liyanli@shu.edu.cn.
¹¹ Cancer Institute, Fudan University Shanghai Cancer Center and Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: yanggong@fudan.edu.cn.

PMID: 37217070
DOI: 10.1016/j.canlet.2023.216241

Abstract

Platinum-taxane chemotherapy is the first-line standard-of-care treatment administered to patients with epithelial ovarian cancer (EOC), and faces the major challenge of cisplatin resistance. Aurora Kinase A (AURKA) is a serine/threonine kinase, acting as an oncogene by participating in microtubule formation and stabilization. In this study, we demonstrate that AURKA binds with DDX5 directly to form a transcriptional coactivator complex to induce the transcription and upregulation of an oncogenic long non-coding RNA, TMEM147-AS1, which sponges hsa-let-7b/7c-5p leading to the increasing expression of AURKA as a feedback loop. The feedback loop maintains EOC cisplatin resistance via activation of lipophagy. These findings underscore the feedback loop of AURKA/DDX5/TMEM147-AS1/let-7 provides mechanistic insights into the combined use of TMEM147-AS1 siRNA and VX-680, which can help improve EOC cisplatin treatment. Our mathematical model shows that the feedback loop has the potential to act as a biological switch to maintain on- (activated) or off- (deactivated) status, implying the possible resistance of single use of VX-680 or TMEM147-AS1 siRNA. The combined use reduces both the protein level of AURKA using TMEM147-AS1 siRNA and its kinase activity using VX-680, showing more significant effect than the use of TMEM147-AS1 siRNA or VX-680 alone, which provides a potential strategy for EOC treatment.

Keywords: AURKA/DDX5; Cisplatin resistance; Epithelial ovarian cancer; Lipophagy; TMEM147-AS1.

Publication types

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

MeSH terms

Aurora Kinase A / genetics
Aurora Kinase A / metabolism
Autophagy
Carcinoma, Ovarian Epithelial / drug therapy
Carcinoma, Ovarian Epithelial / genetics
Cell Line, Tumor
Cell Proliferation
Cisplatin / metabolism
Cisplatin / pharmacology
DEAD-box RNA Helicases / genetics
Feedback
Female
Gene Expression Regulation, Neoplastic
Humans
MicroRNAs* / genetics
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics
RNA, Long Noncoding* / genetics
RNA, Small Interfering

Substances

Cisplatin
Aurora Kinase A
RNA, Small Interfering
RNA, Long Noncoding
MicroRNAs
Ddx5 protein, human
DEAD-box RNA Helicases
AURKA protein, human