Abstract PR002: Ferroptosis inducers can antagonize prostate cancer-bone interactions
Authors: Dike Precious Elechi , Campbell Taaliah , Odero-Marah Valerie 
Published: December 2023

Abstract
Prostate cancer (PCa) is a leading cause of mortality, primarily due to its ability to metastasize to the bone. The incidence, rates of metastasis and mortality rates are higher in men of African descent compared to other races. The transcription factor High Mobility Group AT-Hook 2 (HMGA2) plays a crucial role in regulating gene expression and has been implicated in tumorigenesis and the metastatic process. Our recent study revealed that overexpression of the wild-type/full-length HMGA2 isoform in PCa cells promotes cancer progression by triggering epithelial mesenchymal transition (EMT), whereas truncated HMGA2 isoform promotes progression through oxidative stress signaling. Ferroptosis is a regulated form of cell death induced by the accumulation of iron-dependent lipid reactive oxygen species (ROS). Exploiting this oxidative stress pathway offers a promising therapeutic approach for cancer treatment, especially for apoptosis-resistant cancer cells. In our investigation, we aimed to assess the effectiveness of RSL3, a known ferroptosis inducer, in inhibiting interactions between prostate cancer cells and bone. To achieve this, we co-cultured various human PCa cell lines: C4-2B (Caucasian/bone metastatic), C4-2B MDVR (enzalutamide-resistant), MDAPCa-2b (African American/bone metastatic), LNCaP (Caucasian/non-metastatic) that stably overexpresses Neo control, HMGA2 wild-type or truncated isoform with human ground bone matrix powder (GBM) to recapitulate the bone microenvironment. We collected the conditioned media (CM) from these co-cultures and subsequently added it to parental LNCaP cells, with or without RSL3 ferroptosis inducer, plus or minus Ferrostatin-1 (Fer-1) ferroptosis inhibitor. We then assessed cell viability, migration, and lipid ROS levels. Our results demonstrated that LNCaP cells treated with CM from cancer cells co-cultured with GBM exhibited increased cell viability and migration. However, the addition of RSL3 effectively inhibited cell viability by inactivating GPX4 antioxidant and triggering lipid ROS production; this could be reversed by Fer-1. This suggests that ferroptosis inducers such as RSL3 hold potential as a treatment strategy for prostate cancer bone metastasis. Further investigation is necessary to comprehensively evaluate the impact of RSL3 treatments and elucidate the underlying mechanisms involved. By exploring these avenues, we can advance our understanding and potentially develop targeted therapies to combat the devastating effects of prostate cancer bone metastasis. Acknowledgements: These studies were supported by NIH/NIGMS/RISE SR25GM060414 and NIH/NIMHD 2U54MD007590; 5U54MD013376.
Citation Format: Precious Elechi Dike, Taaliah Campbell, Valerie Odero-Marah. Ferroptosis inducers can antagonize prostate cancer-bone interactions [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr PR002.