CircPAN3 contributes to drug resistance in acute myeloid leukemia through regulation of autophagy. (October 2019)

• Record Type: Journal Article
• Authors: Shang, Jin; Chen, Wei-Min; Liu, Shan; Wang, Zhi-Hong; Wei, Tian-Nan; Chen, Zhi-Zhong; Wu, Wen-Bing
• Is Part Of: Leukemia research. Volume 85(2019)
• Publication Date: 2019-10
• Subjects: circPAN3 circular RNA PAN3 -- AML acute myeloid leukemia -- miRNAs microRNAs -- siRNA small interfering RNA -- Ara-C cytarabine -- CR complete remission -- ncRNA non-coding RNA -- RBP RNA-binding protein -- ADM doxorubicin -- AMPK AMP-activated protein kinase -- p-AMPK phosphorylated AMPK -- p-mTOR phosphorylated mTOR -- CCK-8 Cell Counting Kit-8 -- 3-MA 3-methyladenine -- BM bone marrow -- IC50 half maximal inhibitory concentration -- TMM trimmed mean of M-value -- mRFP monomeric red fluorescent protein -- GFP green fluorescent protein -- qRT-PCR quantitative real-time PCR -- SD standard deviation -- MRE miRNA response element; Acute myeloid leukemia -- Drug resistance -- Circular RNA -- Autophagy -- RNA sequencing; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2019.106198
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: CircPAN3 is a key mediator in the development of AML drug resistance. CircPAN3 facilitates AML drug resistance through regulating autophagy. CircPAN3 regulates autophagy via AMPK/mTOR signaling. Abstract: The aim of this study was to investigate the role and underlying mechanism of circular RNA (circRNA) circPAN3 in mediating drug resistance in acute myeloid leukemia (AML). We first established two doxorubicin (ADM)-resistant AML cell lines and then utilized high-throughput RNA sequencing (RNA-seq) to compare their circRNA expression profiles with those of the parental cell lines. With bioinformatic analysis, we identified key circRNA molecules involved in drug resistance and validated our findings in clinical specimens. The target microRNAs (miRNAs) and downstream mRNAs were also explored bioinformatically. Using RNA interference technique, the potential mechanism was further investigated. Twenty-nine circRNAs were identified to be differentially expressed between ADM-resistant and sensitive cells. We found that circPAN3 is most likely a key mediator in the development of AML drug resistance, evidenced by the increased expression in ADM-resistant cell lines and BM samples from relapsed patients. Additionally, downregulation of circPAN3 by small interfering RNA (siRNA) significantly restored drug sensitivity to ADM in the two ADM-resistant cell lines, but lentivirus-mediated circPAN3 overexpression had the opposite effect. Subsequent bioinformatic analysis and mechanistic experiments revealed that circPAN3 may facilitate AML drug resistance through regulating autophagy and influencing expression of apoptosis-related proteins, while AMPK/mTOR signaling plays a key role in the regulation of circPAN3 on autophagy. These findings may provide new important insights into the role of circRNAs in mediating AML drug resistance, and suggest that circPAN3 might be a potential target for treatment of drug-resistance AML, which merits further investigation and validation.