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PlexinB1 Promotes Nuclear Translocation of the Glucocorticoid Receptor

Magali Williamson1, Ritu Garg1, Claire M Wells1

  • 1School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, New Hunts House, Guys Campus, King's College London, London SE1 1UL, UK.

Cells
|December 22, 2019
PubMed

Insights

Activation of PlexinB1 by semaphorins promotes nuclear entry of the glucocorticoid receptor (GR) in prostate cancer cells. This pathway may contribute to resistance against androgen deprivation therapy (ADT).

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Androgen receptor (AR) and glucocorticoid receptor (GR) are nuclear receptors crucial for gene transcription.
  • Both AR and GR play roles in treatment resistance for advanced prostate cancer, particularly androgen deprivation therapy (ADT).
  • PlexinB1, a semaphorin receptor, is implicated in various cancers and ADT resistance.

Purpose of the Study:

  • To investigate the role of PlexinB1 activation in the nuclear translocation and function of the glucocorticoid receptor (GR) in prostate cancer cells.
  • To determine if PlexinB1 signaling influences resistance to androgen deprivation therapy (ADT).

Main Methods:

  • Prostate cancer cells were treated with Sema4D and Sema3C to activate PlexinB1.
  • Nuclear translocation of endogenous GR and GR-GFP was assessed, including experiments with mutated GR nuclear localization sequence (NLS1).
  • PlexinB1 knockdown was performed, followed by analysis of glucocorticoid-responsive gene products and cell motility/area changes upon dexamethasone treatment.

Main Results:

  • Activation of PlexinB1 by Sema4D and Sema3C induced nuclear translocation of endogenous GR in prostate cancer cells.
  • This effect was dependent on PlexinB1 expression and mediated through the importin α/β system.
  • PlexinB1 knockdown reduced glucocorticoid-responsive gene products and counteracted dexamethasone-induced changes in cell motility and area.

Conclusions:

  • PlexinB1 activation by semaphorins regulates the nuclear trafficking and activation of the glucocorticoid receptor (GR).
  • This PlexinB1-GR signaling pathway is functionally significant in prostate cancer cells.
  • The findings suggest PlexinB1 plays a role in resistance to androgen deprivation therapy (ADT) in advanced prostate cancer.
Keywords:
Plexindexamethasoneglucocorticoid receptornuclear localization signalnucleocytoplasmic traffickingprostate cancersemaphorin

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