Targeting SCD in SCD-amplified prostate cancer inhibits growth in bone by modulating cellular stress, mTOR, and DNA damage pathways

ABSTRACT The bone microenvironment is abundant in adipocytes and fosters metastatic progression, but the underlying mechanisms are not fully understood. We hypothesize that Stearoyl-Coenzyme A Desaturase (SCD) acts as a tumor-promoting enzyme by modulating cellular stress to support the growth and survival of prostate cancer (PCa) in bone. We observe that SCD-amplified PCa cells are highly sensitive to SCD loss and show reduced PCa spheroid size, diminished mTOR signaling, and increased ER stress. Notably, SCD expression is further increased by adipocytes in SCD-amplified cell lines, and its loss increases DNA damage and activates repair pathways in PCa cells only when exposed to adipocytes. Furthermore, we observe PCa cell lines utilize SCD to regulate adipocyte-induced lipid peroxidation. Aligned with these results, pharmacological SCD inhibition in mice bearing SCD-amplified bone tumors reduces tumor size and reveals histochemical evidence of increased ER stress and DNA damage. Collectively, our data highlight the impact of SCD loss on SCD-amplified tumors and suggest germline characteristics of tumors may dictate their response to redox insult and the possibility of targeting DNA repair pathways in combination with SCD inhibition.