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Research Paper|Volume 12, Issue 20|pp 20111—20126

MicroRNA-143 sensitizes acute myeloid leukemia cells to cytarabine via targeting ATG7- and ATG2B-dependent autophagy

Hao Zhang1, Jianmin Kang2, Ling Liu1, Lulu Chen3, Saisai Ren1, Yanling Tao4
  • 1Department of Hematology, Affiliated Hospital of Jining Medical University, Jining 272029, Shandong Province, China
  • 2Department of Hematology, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China
  • 3Graduate School, Jining Medical University, Jining 272000, Shandong Province, China
  • 4Department of Pediatric Hematology, Affiliated Hospital of Jining Medical University, Jining 272029, Shandong Province, China
* Equal contribution
Received: January 28, 2019Accepted: June 24, 2020Published: October 19, 2020
https://doi.org/10.18632/aging.103614

Copyright: © 2020 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Targeting autophagy holds promise to enhance chemosensitivity in acute myeloid leukemia (AML). MicroRNA-143 (miR-143) has been found to suppress autophagy, however, it is not clear whether miR-143 augments cytarabine cytotoxicity in AML. Here, we report that cytarabine treatment reduces miR-143 expression in AML cell lines and primary AML cells. Moreover, ectopic expression of miR-143 further decreases cell viability in cytarabine-treated AML cells. By contrast, miR-143 knockdown inhibits cytarabine-induced cytotoxicity, together indicating a role of miR-143 in enhancing cytarabine sensitivity in AML. Subsequently, we show that miR-143 inhibits autophagy in cytarabine-treated AML cells by directly targeting autophagy-related proteins (ATG), ATG7 and ATG2B, two critical known components of autophagic machinery. More importantly, autophagy reconstructed via co-expression of ATG7 and ATG2B substantially attenuates miR-143-enhanced cytotoxicity, which is associated with suppression of caspase-dependent apoptotic pathway. Overall, this study demonstrates that targeting ATG7 and ATG2B-dependent autophagy is a critical mechanism by which miR-143 sensitizes AML to cytarabine, implicating it as a potential therapeutic target in AML treatment.