Snail transcription factor can promote cancer cell migration and progression by inducing epithelial mesenchymal transition (EMT), a process by which epithelial markers such as E-cadherin are lost, and mesenchymal markers such as vimentin are acquired. 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 RANKL, cathepsin-S and -L. RANKL and cathepsin-L have been previously implicated in bone resorption. ARCaP cells overexpressing Snail could induce osteoclastogenesis both in vitro and in vivo, as compared to ARCaP cells with control Neo vector. Maspin is a tumor suppressor frequently lost in breast and prostate cancer. We have observed an inverse relationship between Snail and maspin expression in vitro. We hypothesize that Snail-mediated upregulation of cathepsin-S and -L, and downregulation of maspin is important for prostate cancer progression and bone metastatic tumor growth and that inhibiting Snail signaling may be a feasible alternative to treat hormone refractory and bone metastatic lesions with less side effects. Firstly, the role and mechanism of Snail-mediated cathepsin expression in prostate tumor progression will be analyzed and whether this pathway is more active in African Amercians as compard to Caucasians (Specific Aim 1). Secondly, the mechanism by which Snail negatively regulates maspin will be elucidated (Specific Aim 2). Finally, whether Snail signaling, especially in an African American prostate cancer cell line, promotes migration to higher bone density and metastasis will be examined, as well as antagonism of Snail signaling utilizing cathepsin inhibitors to investigate whether this prevents bone tumor growth (Specific Aim 3). 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, thus avoiding side effects such as osteonecrosis of the jaw.
These studies will show that Snail can regulate multiple processes (migration, bone resorption, matrix degradation, metastasis to bone) by regulating expression of proteins (cathepsin-S and L, maspin) it had not been previously associated with, especially in African American men who have a higher incidence and more aggressive prostate cancer.
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|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|
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