Oxidative stress is increased in several cancers including prostate cancer, and is currently being exploited in cancer therapy to induce ferroptosis, a novel nonapoptotic form of cell death. High mobility group A2 (HMGA2), a non-histone protein up-regulated in several cancers, can be truncated due to chromosomal rearrangement or alternative splicing of HMGA2 gene. The purpose of this study is to investigate the role of wild-type vs. truncated HMGA2 in prostate cancer (PCa). We analyzed the expression of wild-type vs. truncated HMGA2 and showed that prostate cancer patient tissue and some cell lines expressed increasing amounts of both wild-type and truncated HMGA2 with increasing tumor grade, compared to normal epithelial cells. RNA-Seq analysis of LNCaP prostate cancer cells stably overexpressing wild-type HMGA2 (HMGA2-WT), truncated HMGA2 (HMGA2-TR) or empty vector (Neo) control revealed that HMGA2-TR cells exhibited higher oxidative stress compared to HMGA2-WT or Neo control cells, which was also confirmed by analysis of basal reactive oxygen species (ROS) levels using 2′, 7′-dichlorofluorescin diacetate (DCFDA) dye, the ratio of reduced glutathione/oxidized glutathione (GSH/GSSG) and NADP/NADPH using metabolomics. This was associated with increased sensitivity to RAS-selective lethal 3 (RSL3)-induced ferroptosis that could be antagonized by ferrostatin-1. Additionally, proteomic and immunoprecipitation analyses showed that cytoplasmic HMGA2 protein interacted with Ras GTPase-activating protein-binding protein 1 (G3BP1), a cytoplasmic stress granule protein that responds to oxidative stress, and that G3BP1 transient knockdown increased sensitivity to ferroptosis even further. Endogenous knockdown of HMGA2 or G3BP1 in PC3 cells reduced proliferation which was reversed by ferrostatin-1. In conclusion, we show a novel role for HMGA2 in oxidative stress, particularly the truncated HMGA2, which may be a therapeutic target for ferroptosis-mediated prostate cancer therapy.

Research partnerships between universities and communities following the principles of community-based participatory research (CBPR) have the potential to eliminate cycles of health disparities. The purpose of this article is to describe the process of establishing a community-campus network with a distinct mission and vision of developing trusting and successful research partnerships that are sustained and effective. In 2019, Morgan CARES was established to facilitate community engagement by founding a community center “within” a low-income residential neighborhood as a safe and accessible hub for creating a vibrant learning community. A community needs assessment and asset mapping was conducted and several necessary resources and services were provided to maximize networking opportunities, nurture innovative ideas and proposals, and provide seed funding. Lessons learned informed the optimization of a theoretical model that has guided the development and implementation of the program’s key components. By December 2021, Morgan CARES had recruited 222 community and 137 academic members representing diverse expertise from across Baltimore City. We also successfully established new partnerships and funded a total of 17 small community-academic awards. Although in its early stages, Morgan CARES has established a dynamic learning community following a conceptual framework that could guide future similar initiatives.

Epithelial–mesenchymal transition (EMT), a key event in cancer metastasis, allows polarized epithelial cells to assume mesenchymal morphologies, enhancing invasiveness and migration, and can be induced by reactive oxygen species (ROS). Val16A (Ala) SOD2 polymorphism has been associated with increased prostate cancer (PCa) risk. We hypothesized that SOD2 Ala single nucleotide polymorphism (SNP) may promote EMT. We analyzed SOD2 expression and genotype in various prostate cell lines. Stable overexpression of Ala-SOD2 or Val-SOD2 allele was performed in Lymph Node Carcinoma of the Prostate (LNCaP) cells followed by analysis of intracellular ROS and EMT marker protein expression. Treatments were performed with muscadine grape skin extract (MSKE) antioxidant, with or without addition of H₂O₂ to provide further oxidative stress. Furthermore, MTS cell proliferation, cell migration, and apoptosis assays were completed. The results showed that SOD2 expression did not correlate with tumor aggressiveness nor SOD2 genotype. We demonstrated that the Ala-SOD2 allele was associated with marked induction of EMT indicated by higher Snail and vimentin, lower E-cadherin, and increased cell migration, when compared to Val-SOD2 allele or Neo control cells. Ala-SOD2 SNP cells exhibited increased levels of total ROS and superoxide and were more sensitive to co-treatment with H₂O₂ and MSKE, which led to reduced cell growth and increased apoptosis. Additionally, MSKE inhibited Ala-SOD2 SNP-mediated EMT. Our data indicates that treatment with a combination of H₂O₂-generative drugs, such as certain chemotherapeutics and antioxidants such as MSKE that targets superoxide, hold promising therapeutic potential to halt PCa progression in the future.

In the era of targeted therapeutics, the inadequate representation of Black populations in prostate cancer models limits effective drug screening. In this study, we introduce ACRJ-PC28, a novel Afro-Caribbean prostate cancer cell line, and evaluate its responses to five anticancer drugs (docetaxel, cabazitaxel, abiraterone, olaparib, and enzalutamide) and betaine. We compare these responses with those of established prostate cancer cell lines from Black (MDA-PCA-2b) and White (DU-145 and PC-3) donors using three distinct viability assays. We observed ancestry-dependent drug sensitivities: abiraterone showed remarkable selectivity for ACRJ-PC28 (IC50 = 1.10 μmol/L), being 4.6- to 13.1-fold more potent than in other cell lines, whereas enzalutamide demonstrated pronounced racial differences, being 3 to 5 times less effective in cell lines from Black donors (IC50 = 206 μmol/L for ACRJ-PC28; 104 μmol/L for MDA-PCA-2b) versus cell lines from White donors (IC50 = 37 μmol/L for PC-3; 48 μmol/L for DU-145). RNA sequencing analysis revealed consistent underexpression of TNF family genes, particularly TNFRSF14, in prostate cancer cells from Black donors correlating with differential drug responses. Despite underexpressing AR, the ACRJ-PC28 line exhibited exceptional sensitivity to abiraterone, consistent with clinical observations that Black patients with prostate cancer respond better to this therapy. This aligns with its neuroendocrine phenotype in the source patient, who succumbed within 1 year despite androgen deprivation therapy. Our findings suggest that incorporating diverse prostate cancer models in preclinical screening could guide personalized treatment strategies for Black patients who experience disproportionate prostate cancer mortality by identifying ancestry-specific drug vulnerabilities that inform optimal therapeutic combinations. Significance: This study introduces ACRJ-PC28, the first Afro-Caribbean prostate cancer cell line, revealing ancestry-dependent drug sensitivities that could explain differential clinical outcomes. The findings demonstrate critical gaps in current preclinical models and support incorporating diverse cell lines to develop personalized treatment strategies for underrepresented populations experiencing disproportionate cancer mortality.