Snail in prostate cancer cells promotes neurite outgrowth, 2021
Edwards, Gabrielle
2021-05
2020-2029
Most men who die of prostate cancer suffer from distant organ metastatic disease. Epithelial mesenchymal transition (EMT) is characterized as a critical step for cell trans-differentiation and is involved in the migration or metastatic cascade of many solid tumors. EMT can be induced by Snail transcription factor, a zinc-finger protein that can down-regulate cell adhesion proteins such as E-cadherin and up-regulate mesenchymal proteins thus promoting tumor migration and metastasis. Recently, studies have focused on metastatic spread within the nervous system as a possible factor of prostate cancer metastasis; however, the potential underlying mechanisms are poorly understood. We hypothesized that cancer cell migration and interaction with nerve cells is mediated by Snail. Neurite outgrowth is a process where developing neurons produce new tentacle-like extensions as they grow in response to guidance cues. The projection can be an axon or a dendrite (nerve fibers). Therefore, the concept of neoneurogenesis includes the development of nerve endings (axons) towards the tumor. Neurite outgrowth involves reciprocal signaling interactions between tumor cells and nerves where invading tumor cells have acquired the ability to respond to pro-invasive signals within the peripheral nerve environment. To test our hypothesis, we utilized prostate cancer cell models engineered to express low or high expression of Snail, followed by neurite outgrowth assays, and analysis of mechanisms involved in the neurite outgrowth. Our results showed that C42 non silencing (NS) prostate cancer cells that express high levels of Snail, and LNCaP Snail (cells stably overexpressing Snail) conditioned media when added to PC12 and NS20Y nerve cells led to a higher neurite outgrowth from these nerve cells, compared to the Snail knockdown cells (C42 snail shRNA) and LNCaP Neo (control with low Snail). Additionally, C4-2 NS cells secreted microvesicles containing WD Repeat Domain 77 (MEP50) WDR77, and Talin1. We also observed that neurite outgrowth was blocked by C9, a drug that inhibits the WDR77/PRMT5 complex,10D2 anti-short Talin-antibody, and mH4 Talin protease inhibitors. In conclusion, Snail promotes neurite outgrowth, which can be inhibited by PRMT5 and Talin inhibitors. Therefore, targeting cancer cell interaction with nerve cells may be helpful in halting prostate cancer progression/metastasis.
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Atlanta University and Clark Atlanta University Theses and Dissertations
dissertation
Doctor of Philosophy (PhD)
Clark Atlanta University
Department of Biological Sciences
Odero-Marah, Valerie
Georgia--Atlanta
http://hdl.handle.net/20.500.12322/cau.td:2021_edwards_gabrielle
http://rightsstatements.org/vocab/InC-EDU/1.0/
