Snail promotes resistance to enzalutamide through regulation of androgen receptor activity in prostate cancer

Abstract

Treatment with androgen-targeted therapies can induce upregulation of epithelial plasticity pathways. Epithelial plasticity is known to be important for metastatic dissemination and therapeutic resistance. The goal of this study is to elucidate the functional consequence of induced epithelial plasticity on AR regulation during disease progression to identify factors important for treatment-resistant and metastatic prostate cancer. We pinpoint the epithelial plasticity transcription factor, Snail, at the nexus of enzalutamide resistance and prostate cancer metastasis both in preclinical models of prostate cancer and in patients. In patients, Snail expression is associated with Gleason 9-10 high-risk disease and is strongly overexpressed in metastases as compared to localized prostate cancer. Snail expression is also elevated in enzalutamide-resistant prostate cancer cells compared to enzalutamide-sensitive cells, and downregulation of Snail re-sensitizes enzalutamide-resistant cells to enzalutamide. While activation of Snail increases migration and invasion, it is also capable of promoting enzalutamide resistance in enzalutamide-sensitive cells. This Snail-mediated enzalutamide resistance is a consequence of increased full-length AR and AR-V7 expression and nuclear localization. Downregulation of either full-length AR or AR-V7 re-sensitizes cells to enzalutamide in the presence of Snail, thus connecting Snail-induced enzalutamide resistance directly to AR biology. Finally, we demonstrate that Snail is capable of mediating-resistance through AR even in the absence of AR-V7. These findings imply that increased Snail expression during progression to metastatic disease may prime cells for resistance to AR-targeted therapies by promoting AR activity in prostate cancer.

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

“…Based on our preclinical data and these observations, we hypothesized that p38 activation would be associated with aggressive and metastatic disease. To test our hypothesis we compared, by immunohistochemistry, 30 primary tumors and 20 metastatic biopsies from prostate cancer patients (Ware et al, 2016) for phospho-p38 expression. These tumors were all positive for AR expression.…”

“…To better understand the mechanisms by which p38 activity may promote metastasis, we interrogated known drivers of metastatic prostate cancer. One of these drivers of metastasis is Snail, a master regulator of epithelial plasticity that promotes migration and invasion and is strongly expressed in 100% of metastatic prostate cancer biopsies (Ware et al, 2016). We have previously shown that Snail activates AR nuclear localization to drive plasticity, invasion, and enzalutamide resistance (Ware et al, 2016).…”

EMT and MET: necessary or permissive for metastasis?

“…Overexpression of Snail in MDCK and many carcinoma cell lines led to loss of cell-cell adhesion mediated by E-cadherin, transformed the morphology of cells from epithelial to spindle-liked mesenchymal, and enhanced their migratory and invasive traits in vitro (Batlle et al, 2000;Cano et al, 2000). Further work revealed a similar, but less potent role of another EMT-TF Slug (SNAI2, a member of Snail family) both in vitro and in vivo (Bolós et al, 2003;Hajra et al, 2002;Ware et al, 2016). Snail was also shown to induce the expression of mesenchymal markers fibronectin and Zeb1 (Guaita et al, 2002), the latter of which is another EMT-TF that can promote tumor invasiveness in vitro and is correlated with tumor cell differentiation in vivo (Aigner et al, 2007;.…”

Cellular determinants and microenvironmental regulation of prostate cancer metastasis

“…Twist1/AR signaling is also augmented in castration resistant as well as mesenchymal-type PCa, indicating the molecular mechanism of mutual and functional crosstalk between EMT and castration resistance [125]. The EMT master regulator, Snail, promotes enzalutamide resistance and mPCa, as a consequence of increased full-length AR and AR-V7 expression and nuclear localization, in preclinical models of PCa and in patients [126]. On the other hand, ligand-activated AR regulates expression of several key EMT factors whereas antiandrogens counteract AR activity only on selected EMT genes [127].…”