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.

中文翻译：

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超生理睾酮通过前列腺癌中的核吞噬诱导铁死亡并激活免疫途径

雄激素在前列腺癌的进展中发挥重要作用的发现导致了雄激素剥夺疗法（ADT）作为一线治疗的发展。然而，在实验和临床上，在给予超生理水平的睾酮 (SupraT) 后，在前列腺癌的一个子集中观察到了矛盾的生长抑制。在这里，我们报告 SupraT 激活细胞质核酸传感器并诱导 SupraT 敏感前列腺癌细胞的生长抑制。这是由两个平行的自噬介导的过程（即铁蛋白自噬和核自噬）的诱导引发的。因此，自噬体 DNA 激活的核酸传感器聚集在 NFκB 上以驱动免疫信号通路。在异种移植模型和患者肿瘤中，肿瘤细胞响应 SupraT 分泌的趋化因子和细胞因子导致细胞毒性免疫细胞向肿瘤床的迁移增加。总的来说，这些发现表明 SupraT 可能通过激活核酸传感器和下游免疫信号来抑制前列腺癌的子集。意义：这项研究表明，超生理睾酮诱导两个平行的自噬介导的过程，即铁蛋白自噬和核自噬，然后激活核酸传感器以驱动前列腺癌中的免疫信号通路。