Effect of TGF-β mediated phenotypic changes on prostate cancer cell anoikis response.

Epithelial mesenchymal transition (EMT) circumvents anoikis (cell death upon detachment from extracellular matrix) to promote prostate metastasis and therapy resistance. In this study, we investigated how TGF-β regulated EMT-MET (mesenchymal epithelial transition) phenotypic interconversions to enhance anoikis response in pre-clinical models of prostate cancer (PCa). We used human PCa cell line models: VCaP (androgen-sensitive, TGF-β responsive); 22RV1 (castration resistant prostate cancer); LNCaP; LNCaPTβRII (LNCaP cells overexpressing TGF-β receptor II, androgen-sensitive, TGF-β responsive); C4-2B parental and C4-2B TaxR (TGF-β unresponsive, taxane resistant). We assessed their response to TGF-β (EMT inducer) and two antitumor agents (DZ-50 and cabazitaxel (CBZ)) to understand the effect of EMT priming on anoikis vulnerability. Our findings demonstrate: (1) TGF-β induces EMT in LNCaPTβRII and apoptosis in VCaP. (2) LNCaPTβRII cells are primed by EMT to anoikis (downregulation of pSRC and cofilin). (3) Metabolic changes occur at EMT-anoikis intersection in LNCaPTβRII. (4) DZ-50 overcomes CBZ resistance in C4-2B TaxR and improves response in cells and castration-resistant organoids. These studies indicate that prostate cancer cells "programmed" to undergo phenotypic EMT become vulnerable to cell death via anoikis. Exploitation of this intersection is of potential significance in overcoming resistance to taxane chemotherapy in lethal prostate cancer. The intersection between EMT and anoikis in prostate cancer cells. TGF-β responsive prostate cancer cells respond differentially to TGF-β by undergoing epithelial mesenchymal transition EMT (LNCaPTβRII and VCaP) or apoptosis (VCaP). TGF-β induced EMT further sensitizes LNCaPTβRII to DZ-50 induced anoikis. DZ-50-associated anoikis cell death in prostate cancer cells is associated with (i) phenotypic reprogramming (EMT to mesenchymal epithelial transition (MET)) (ii) inactivation of SRC (decreased pSRC) (iii) decreased cofilin expression in LNCaPTβRII and VCaP cells.