Snail transcription factor is important early in development and in cancer cells and promotes cancer cell migration and progression by inducing epithelial mesenchymal transition (EMT). We have observed increased expression of Snail in prostate cancer bone metastatic human patient samples. We recently generated an EMT model for prostate cancer utilizing the ARCaP human prostate cancer cells overexpressing Snail and identified increased receptor activator for NF?B ligand (RANKL) and cathepsin-L (Cat L). These cells could induce osteoclastogenesis both in vitro and in vivo. African American men have higher bone mineral density than any other race and also present with more aggressive prostate cancer than any other race. We hypothesize that Snail can mediate EMT-mediated prostate cancer migration towards bone of high bone mineral density and mediate the vicious cycle of tumor-tumor microenvironment reciprocal interactions through calcium, Cat L, and RANKL signaling, resulting in tumor growth and increased osteoclastogenesis. Firstly, the role and mechanism of Snail-mediated Cat L expression in prostate tumor progression will be analyzed (Specific Aim 1). Secondly, the role of Snail in migration towards high bone mineral density will be examined and whether calcium release from bone degradation stimulates more RANKL and Cat L expression/activity and tumor growth (Specific Aim 2). Since Snail is not required by adult cells except during injury, targeting Snail that is mainly expressed by cancer cells may antagonize metastatic lesions in bone without affecting normal bone in other areas of the body.
Snail transcription factor can induce epithelial-mesenchymal transition (EMT), a process associated with expression of certain proteins that promotes migration and metastasis of cancer. We have also found that Snail turns on proteins associated with bone, and since African American men have more dense bone than any other race and present with more aggressive prostate cancer, we hypothesize that Snail signaling may promote migration and colonization of dense bone. This study will show that Snail may be a beneficial target to prevent aggressive prostate cancer progression such as is seen in African American men.
|Wilder, Catera L; Walton, Charlene; Watson, Valencia et al. (2016) Differential cathepsin responses to inhibitor-induced feedback: E-64 and cystatin C elevate active cathepsin S and suppress active cathepsin L in breast cancer cells. Int J Biochem Cell Biol 79:199-208|
|Burton, Liza J; Smith, Basil A; Smith, Bethany N et al. (2015) Muscadine grape skin extract can antagonize Snail-cathepsin L-mediated invasion, migration and osteoclastogenesis in prostate and breast cancer cells. Carcinogenesis 36:1019-27|