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Transcriptional Up-Regulation of FBXW7 by KCa1.1 K+ Channel Inhibition through the Nrf2 Signaling Pathway in Human

Susumu Ohya1, Hiroaki Kito1, Junko Kajikuri1

  • 1Department of Pharmacology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.

International Journal of Molecular Sciences
|June 19, 2024
PubMed

Insights

Inhibiting the KCa1.1 channel in prostate cancer cells boosts FBXW7 activity, suppressing cancer stemness by degrading c-Myc. This reveals a new pathway targeting cancer stem cell conversion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The F-box and WD repeat domain-containing 7 (FBXW7) tumor suppressor gene inhibits cancer stemness by degrading pluripotent stem cell markers.
  • Cancer cell 3D spheroid formation represses FBXW7 transcription.
  • Prostate cancer stemness is a therapeutic target.

Purpose of the Study:

  • To investigate the regulation of FBXW7 transcriptional activity in a 3D spheroid model of human prostate cancer LNCaP cells.
  • To elucidate the role of the Ca2+-activated K+ channel, KCa1.1, in FBXW7 regulation and cancer stem cell (CSC) properties.

Main Methods:

  • Utilized a 3D spheroid model of human prostate cancer LNCaP cells.
  • Investigated the effects of KCa1.1 inhibition on FBXW7 transcriptional activity via the Akt-Nrf2 signaling pathway.
  • Employed siRNA-mediated inhibition of CEBPD and miR223 mimics to explore the regulatory axis.
  • Assessed KCa1.1 activity, protein levels, and CSC marker c-Myc levels.

Main Results:

  • KCa1.1 inhibition promoted FBXW7 transcriptional activity in LNCaP spheroids through the Akt-Nrf2 pathway.
  • FBXW7 transcription was regulated by an Akt-Nrf2-CEBPD-miR223 axis.
  • KCa1.1 inhibition-induced FBXW7 activation reduced KCa1.1 activity and plasma membrane levels.
  • FBXW7 activation decreased c-Myc protein levels, a key CSC marker degraded by FBXW7.

Conclusions:

  • KCa1.1 inhibition activates FBXW7 transcription, suppressing CSC conversion in KCa1.1-positive prostate cancer cells.
  • The Akt-Nrf2-CEBPD-miR223 axis plays a crucial role in regulating FBXW7 transcription in this model.
  • Targeting KCa1.1 presents a potential therapeutic strategy to reduce cancer stemness in prostate cancer.
Keywords:
C/EBPCa2+-activated K+ channelFBXW7KCa1.1Nrf2c-Myccancer stemnessmiR223protein degradationspheroid

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