The Environmental Carcinogen Diepoxybutane Modulates the PI3K/AKT/ mTOR and Wnt Cell Signaling Pathways in DU145 Prostate Cancer Cell Organoids

Author(s): Harriet Hammond, Keerthika Yalakaturi, Eduardo Martinez-Ceballos, Xiaoping Yi

Prostate cancer is the most common cancer in men and one of the leading causes of cancer-related deaths worldwide. Multiple factors, including age, lifestyle, genetic, and environmental factors, are associated with increased risk for prostate cancer. Butadiene (BD), an industrial and environmental chemical used in synthetic rubber and plastic manufacturing, is a known human carcinogen and is associated with an increased risk of certain types of cancer in occupational settings. Studies suggest a potential link between exposure to diepoxybutane (DEB), the key carcinogenic metabolite of BD, and the development of prostate cancer. However, further research is needed to clarify the potential association and understand the underlying mechanisms, if any, between exposure to BD and/or its metabolites like DEB, and prostate cancer in humans. The PI3K/AKT/mTOR signaling pathway plays a central role in regulating various cellular processes, including cell growth, survival, and metabolism. Dysregulation of the PI3K/AKT/mTOR pathway is associated with various diseases, including cancer, where excessive activation can lead to uncontrolled cell growth and tumor formation. The main goal of this study is to determine whether DEB exposure disrupts signaling of the PI3K/AKT/mTOR pathway in prostate cancer cells, potentially promoting tumor progression. To achieve this goal, 3D organoid cultures of DU145 prostate cancer cells were treated with various concentrations of DEB. Subsequently, RNA or protein were extracted from both treated and control (untreated) DU145 cells for gene and protein expression analyses, respectively. Our results show that DEB promotes the activation of the PI3K/AKT cell signaling pathway that may occur via the upregulation of cell cycle genes such as CDK1, CDK4, CCNB1 (Cyclin B1), and CCNE1 (Cyclin E1), accompanied by the upregulation of cancer stem cell markers, including OCT3, OCT4, and NANOG. While our data suggests that DEB may promote tumor progression in DU145 prostate cancer cells, more research is needed to uncover the potential genetic factors that contribute to this progression. Results obtained from this project will increase our understanding of the role played by BD and DEB exposure on prostate cancer progression and will contribute to the improvement of prostate cancer prevention, diagnosis, treatment, and overall patient outcomes.