AHR signaling pathway reshapes the metabolism of AML/MDS cells and potentially leads to cytarabine resistance

Acta Biochim Biophys Sin (Shanghai). 2021 Mar 26;53(4):492-500. doi: 10.1093/abbs/gmab017.

Abstract

Emerging evidence suggests that aryl hydrocarbon receptor (AHR) promotes the initiation, invasion, progression, and metastasis of cancer cells. However, its effects in patients with myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) remain undefined. In this study, we aimed to investigate the effects of AHR activation on malignant cells in patients with MDS/AML. We found that AHR was expressed aberrantly in patients with MDS/AML. Further studies demonstrated that inhibiting AHR decreased the mitochondrial dehydrogenase content and the mitochondrial membrane potential (MMP) in MDS/AML cells. Activating AHR with L-kynurenine (Kyn) increased AHR expression, which was accompanied by an increase in mitochondrial dehydrogenase content and MMP in MDS/AML cells. Moreover, the expression level of mitochondria-associated mitochondrial transcription factor A was increased after activating AHR with L-Kyn when compared with that in the control group but decreased after inhibiting the AHR signal. Activating AHR in MDS/AML cells enhanced the resistance to cytarabine. These findings indicated that activating the AHR signaling pathway reshaped the metabolism in MDS/AML cells, thus contributing to the resistance to cytarabine.

Keywords: AHR; AML; MDS; mitochondrial metabolism; resistance.

MeSH terms

  • Adult
  • Aged
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cytarabine / pharmacology*
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / drug therapy
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • THP-1 Cells
  • U937 Cells

Substances

  • AHR protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Neoplasm Proteins
  • Receptors, Aryl Hydrocarbon
  • Cytarabine