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Supraphysiologic Testosterone Induces Ferroptosis and Activates Immune Pathways through Nucleophagy in Prostate

Rajendra Kumar1, Janet Mendonca1, Olutosin Owoyemi1

  • 1The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Cancer Research
|October 14, 2021
PubMed

Insights

Supraphysiologic testosterone (SupraT) paradoxically inhibits some prostate cancers by activating immune signaling. This occurs through inducing ferritinophagy and nucleophagy, which then activate nucleic acid sensors and immune cell migration.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Androgen deprivation therapy (ADT) is a standard prostate cancer treatment.
  • A subset of prostate cancers exhibits paradoxical growth inhibition with supraphysiologic testosterone (SupraT).

Purpose of the Study:

  • To investigate the mechanism by which SupraT inhibits prostate cancer growth.
  • To elucidate the role of autophagy and immune signaling in SupraT-mediated growth inhibition.

Main Methods:

  • Experimental administration of SupraT to prostate cancer models.
  • Analysis of autophagy-mediated processes (ferritinophagy, nucleophagy).
  • Assessment of nucleic acid sensor activation and downstream immune signaling (NFκB, chemokines, cytokines).
  • Evaluation of immune cell infiltration in xenograft and patient tumor samples.

Main Results:

  • SupraT induced ferritinophagy and nucleophagy in sensitive prostate cancer cells.
  • Activated nucleic acid sensors converged on NFκB, driving immune signaling.
  • Secreted chemokines and cytokines promoted cytotoxic immune cell migration to tumors.
  • SupraT demonstrated growth inhibition in a subset of prostate cancer.

Conclusions:

  • Supraphysiologic testosterone inhibits a subset of prostate cancer via activation of cytoplasmic nucleic acid sensors.
  • This inhibition is mediated by parallel autophagy-dependent processes: ferritinophagy and nucleophagy.
  • SupraT treatment triggers tumor cell-intrinsic immune signaling, enhancing anti-tumor immunity.

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