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Supraphysiological testosterone induces ferroptosis and activates NF-kappaB mediated immune pathways in prostate cancer through nucleophagy

By Janet Mendonca, Rajendra Kumar, 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 Isaacs, Angelo M De Marzo, Mark Markowski, Emmanuel S. Antonarakis, David Qian, Kenneth Pienta, Drew Pardoll, Michael Carducci, Samuel Denmeade, Sushant Kachhap

Posted 10 Sep 2020
bioRxiv DOI: 10.1101/2020.09.10.286252

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. ### Competing Interest Statement ESA is a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Pfizer, Amgen, Eli Lilly, Bayer, AstraZeneca, Bristol-Myers Squibb, Clovis, and Merck; and has received research funding from Janssen, Johnson & Johnson, Sanofi, Dendreon, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis, and Merck.

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