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

Abstract

The discovery that androgens play an important role in the progression of prostate cancer led to the development of androgen deprivation therapy (ADT) as a first line of treatment. However, paradoxical growth inhibition has been observed in a subset of prostate cancer upon administration of supraphysiologic levels of testosterone (SupraT), both experimentally and clinically. Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive prostate cancer cells. This was initiated by the induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activated nucleic acid sensors converge on NFκB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT resulted in increased migration of cytotoxic immune cells to tumor beds in xenograft models and patient tumors. Collectively, these findings indicate that SupraT may inhibit a subset of prostate cancer by activating nucleic acid sensors and downstream immune signaling. SIGNIFICANCE: This study demonstrates that supraphysiologic testosterone induces two parallel autophagy-mediated processes, ferritinophagy and nucleophagy, which then activate nucleic acid sensors to drive immune signaling pathways in prostate cancer.

• Authors: Rajendra Kumar, Janet Mendonca, Olutosin Owoyemi, Kavya Boyapati, Naiju Thomas, Suthicha Kanacharoen, Max Coffey, Deven Topiwala, Carolina Gomes, Busra Ozbek, Tracy Jones, Marc Rosen, Liang Dong, Sadie Wiens, W Nathaniel Brennen, John T Isaacs, Angelo M De Marzo, Mark C Markowski, Emmanuel S Antonarakis, David Z Qian, Kenneth J Pienta, Drew M Pardoll, Michael A Carducci, Samuel R Denmeade, Sushant K Kachhap
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 23 Pg. 5948-5962 (12 01 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34645612 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Androgens
• Testosterone

Topics

• Androgens (pharmacology)
• Animals
• Apoptosis
• Autophagy
• Cell Proliferation
• Ferroptosis
• Humans
• Male
• Mice
• Mice, Nude
• Prognosis
• Prostatic Neoplasms (drug therapy, immunology, metabolism, pathology)
• Testosterone (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays