1. Supraphysiological testosterone induces ferroptosis and activates NF-kappaB mediated immune pathways in prostate cancer through nucleophagy
- Author
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Janet Mendonca, Naiju Thomas, Sushant Kachhap, Kavya Boyapati, Liang Dong, Samuel R. Denmeade, Marc Rosen, Emmanuel S. Antonarakis, Carolina Gomes, Drew M. Pardoll, Max Coffey, Kenneth J. Pienta, Angelo M. De Marzo, Rajendra Kumar, Tracy Jones, Sadie Wiens, W. Nathaniel Brennen, Busra Ozbek, Suthicha Kanacharoen, Olutosin Owoyemi, Michael A. Carducci, David Z. Qian, John T. Isaacs, Deven Topiwala, and Mark C. Markowski
- Subjects
Nucleophagy ,Chemokine ,biology ,Chemistry ,medicine.disease ,Androgen deprivation therapy ,Prostate cancer ,chemistry.chemical_compound ,Immune system ,biology.protein ,Cancer research ,medicine ,Cytotoxic T cell ,Growth inhibition ,Testosterone - Abstract
The discovery that androgens play an important role in the progression of prostate cancer (PCa) has led to the development of androgen deprivation therapy as a first line of treatment against PCa. However, paradoxical growth inhibition has been observed, both experimentally and clinically, in a subset of PCa upon administration of supraphysiological levels of testosterone (SupraT). Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive PCa cells. This is initiated by induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activates nucleic acid sensors that converge on NF-kappaB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT results in increased migration of cytotoxic immune cells to tumor beds of animal xenografts and patient tumors. Collectively, our findings indicate that SupraT may inhibit a subset of PCa by activating nucleic acid sensors and downstream immune signaling.
- Published
- 2020