HOTAIRM1 knockdown enhances cytarabine-induced cytotoxicity by suppression of glycolysis through the Wnt/β-catenin/PFKP pathway in acute myeloid leukemia cells
Introduction
Acute myeloid leukemia (AML) is the most common acute forms of leukemia with a poor long-term survival [1]. AML is characterized by the rapid growth of immature myeloid cells and suppression of normal hematopoietic cells in the bone marrow, peripheral blood and other tissues [2]. Prognosis of AML is poor with 5-year survival rates ranging from 5 to 65% depending on demographic and clinical features [3]. In recent years, the first-line treatment of AML consists primarily of chemotherapy. Treatment for AML has remained cytarabine (Ara-C) and an anthracycline (most often daunorubicin) given in the standard 3 + 7 regimen [4]. The Ara-C is given as a continuous IV infusion for seven days, while the anthracycline is given as an IV push for three consecutive days. However, acquired resistance to Ara-C is a major challenge in the clinical management of AML [5]. Therefore, a novel therapeutic approach enhancing the Ara-C cytotoxicity is required for complete cure of AML.
It has been demonstrated that aberrant expression of various non-coding RNAs, such as micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs) is proved to be of seminal importance in the pathogenesis of AML and the development of resistance to chemotherapy [[6], [7], [8], [9]]. The non-coding RNAs act as key players in the regulation of both physiologic and pathologic gene expression profiles. HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) is a lncRNA that is highly specific for maturing myeloid cells. HOTAIRM1 has been found to regulate cell cycle progression during myeloid maturation in NB4 human promyelocytic leukemia cells [10]. Besides, HOTAIRM1 regulates the degradation of PML-RARA oncoprotein and myeloid cell differentiation by enhancing the autophagy pathway, indicating that HOTAIRM1 may be the potential therapeutic target for leukemia [11]. However, the role of HOTAIRM1 in the Ara-C cytotoxicity remains unknown. In the present study, we investigated the effect of HOTAIRM1 on the Ara-C cytotoxicity in leukemia cell lines and explored the underlying mechanism.
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Cell culture and treatments
The AML cell lines HL60 and THP-1 were purchased from American Type Culture Collection (Manassas, VA, USA). Cells were cultured in RPMI 1640 medium (Gibco, Rockville, MD, USA) supplemented with 10% fetal bovine serum (FBS; Gibco), 100 μg/ml streptomycin (Solarbio, Beijing, China) and 100 U/ml penicillin (Solarbio). Cells were grown in humidified air with 5% CO2 at 37 °C. For some experiments, cells were incubated with different concentrations of Ara-C (Sigma-Aldrich, St. Louis, MO, USA).
Knockdown of HOTAIRM1 enhances Ara-C cytotoxicity
We have previously showed that HOTAIRM1 was overexpressed in AML patients than healthy controls [12]. To investigate the role of HOTAIRM1 in AML cells, HL60 and THP-1 cells were transfected with si-HOTAIRM1 to knock down HOTAIRM1. As shown in Fig. 1A, the expression of HOTAIRM1 was decreased after transfection with si-HOTAIRM1 as compared to cells transfected with si-ctrl. HL60 and THP-1 cells were incubated with different concentrations of Ara-C (0, 0.25, 0.5, 1, or 2 μM) for 24, 48, and 72 h.
Discussion
HOTAIRM1 plays a key role during myeloid maturation and highly expresses in AML patients. The higher expression level of HOTAIRM1 is associated with worse prognosis of HOTAIRM1 patients. HOTAIRM1 has been identified as an independent prognostic factor in a large series of intensively treated IR-AML patients [15]. These findings suggest that HOTAIRM1 might play a crucial role in AML leukemogenesis and outcome. Ara-C is a chemotherapy medication that is clinically used to treat AML, chronic
CRediT authorship contribution statement
Li Chen: Conceptualization, Investigation, Data curation, Writing - original draft. Ning Hu: Investigation, Methodology, Formal analysis, Writing - review & editing. Chao Wang: Methodology, Formal analysis, Software. Hongmian Zhao: Conceptualization, Project administration, Supervision, Writing - review & editing.
Declaration of competing interest
All authors declare no conflict of interest.
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