Supraphysiological testosterone induces ferroptosis and activates NF-kappaB mediated immune pathways in prostate cancer through nucleophagy
Year: 2020
Type: preprint
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.
Authors: 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
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1165598027, G1804297005, G2580177631, G4119534169, INNATE IMMUNE SIGNALING INDUCED BY ANDROGENS: IMPLICATIONS IN TUMOR RESPONSE TO BIPOLAR ANDROGEN THERAPY...NEW GRANT, SIGNED: 8/22/2019, DISTRIBUTED: 8/23/2019, FAADC: 8/27/2019, G465951118, G5024835356, G6798853303, BIPOLAR ANDROGEN THERAPY: BREAKING OUT OF THE CHRYSALIS OF CHRONIC ANDROGEN DEPRIVATION THERAPY IN MEN WITH LATE-STAGE CASTRATE-RESISTANT PROSTATE CA
OpenAlex ID: W3083841575