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

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. QianKenneth J. Pienta, Drew M. Pardoll, Michael A. Carducci, Samuel R. Denmeade, Sushant K. Kachhap

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)5948-5962
Number of pages15
JournalCancer Research
Issue number23
StatePublished - Dec 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
We thank Sabatini and Lander for pCW-Cas9 (Addgene#50661) and pLXsgRNA (Addgene#50662), Trono for pMD2.G (Addgene 12259) and psPAX2 (Addgene#12260), and Wade Harper for the NCOA4a-pHAGE-C-FLAG-HA plasmid. This work is supported by the DOD grants W81XWH1910724 to S.K. Kachhap and W81XWH-14-2-0189 to S.R. Denmeade; Allegheny Health Network-Johns Hopkins Cancer Research Fund, and the NCI CORE Grant P30CA006973. E.S. Antonarakis and S.K. Kachhap are partially supported by a PCF 2018 Challenge Award. M. Coffey was supported by the CUPID program at Hopkins. Research reported in this publication was also supported by the Office of the Director of the National Institutes of Health under award number S10OD016374 and S10OD023548.

Funding Information:
J.T. Isaacs reports a patent for Sequential treatment regimen for men with castration-resistant prostate cancer: JHU REF: [C16749] pending. A.M. De Marzo reports personal fees from Cepheid Inc. and Merck, grants from Janssen R&D and Myriad outside the submitted work. E.S. Antonarakis reports personal fees from Amgen, Astellas, Bayer, Eli Lilly; grants and personal fees from AstraZeneca, Bristol Myers-Squibb, Clovis, Janssen, Merck, and Sanofi outside the submitted work. S.R. Denmeade reports a patent for Use of testosterone as therapy for prostate cancer in sequence with antiandrogen pending. S.K. Kachhap reports a patent for C16749_P16749-01 pending. No disclosures were reported by the other authors.

Publisher Copyright:
© 2021 American Association for Cancer Research Inc.. All rights reserved.


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