1. Academic Validation
  2. Overexpressed mitogen-and stress-activated protein kinase 1 promotes the resistance of cytarabine in acute myeloid leukemia through brahma related gene 1-mediated upregulation of heme oxygenase-1

Overexpressed mitogen-and stress-activated protein kinase 1 promotes the resistance of cytarabine in acute myeloid leukemia through brahma related gene 1-mediated upregulation of heme oxygenase-1

  • Eur J Pharmacol. 2022 Feb 15;917:174722. doi: 10.1016/j.ejphar.2021.174722.
Siyu Zhang 1 Chengyun Pan 2 Qin Shang 3 Weili Wang 4 Tianzhen Hu 3 Ping Liu 2 Siyu Chen 5 Jishi Wang 6 Qin Fang 7
Affiliations

Affiliations

  • 1 College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China; Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China.
  • 2 Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
  • 3 College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China.
  • 4 Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China; Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China.
  • 5 Department of Clinical Medical School, Guizhou Medical University, Guiyang, Guizhou, China.
  • 6 Laboratory of Hematopoietic Stem Cell Transplantation Centre of Guizhou Province, Guiyang, Guizhou, China; Department of Haematology, Affiliated Hospital of Guizhou Medical University, Guizhou, China. Electronic address: wangjishi9646@163.com.
  • 7 College of Pharmacy, Guizhou Medical University, Guiyang, Guizhou, China; Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China. Electronic address: 1731998914@qq.com.
Abstract

Drug resistance remains a major challenge in the current treatment of acute myeloid leukemia (AML). Finding specific molecules responsible for mediating drug resistance in AML contributes to the effective reversal of drug resistance. Recent studies have found that mitogen- and stress-activated protein kinase 1 (MSK1) is of great significance in the occurrence and development of tumors. In the current study, MSK1 was found highly expressed in drug-resistant AML patients. Heme oxygenase-1 (HO-1) has been previously validated to be associated with drug resistance in AML. Our study revealed a positive correlation between MSK1 and HO-1 in patient samples. In vitro experiments revealed that the sensitivity of AML cell lines THP-1 and U937 to cytarabine (Ara-C) significantly decreased after overexpression of MSK1. Meanwhile, downregulation of MSK1 by siRNA transfection or treatment of pharmacological inhibitor SB-747651A in AML cell lines and primary AML cells enhanced the sensitivity to Ara-C. Flow cytometry analysis showed that downregulation of MSK1 in AML cells accelerated Apoptosis and arrested cell cycle progression in G0/G1 phase. However, the increased cell sensitivity induced by MSK1 downregulation was reversed by the induction of HO-1 inducer Hemin. Through further mechanism exploration, Real-Time PCR, immunofluorescence and Western blot analysis demonstrated that brahma related gene 1 (BRG1) was involved in the regulatory effect of MSK1 on HO-1. High expression of MSK1 could promote the resistance of AML through BRG1-mediated upregulation of HO-1. Downregulation of MSK1 enhanced the sensitivity of AML cells to Ara-C. Our findings provide novel ideas for developing effective anti-AML targets.

Keywords

Acute myeloid leukemia (AML); Brahma related gene 1 (BRG1); Cytarabine (Ara-C); Drug resistance; Heme oxygenase-1 (HO-1); Mitogen- and stress-activated protein kinase 1 (MSK1).

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