RESUMO
Prostate cancer (PCa) is a key public health problem worldwide; at diagnosis, a high percentage of patients exhibit tumor cell invasion of adjacent tissue. STAT3, IL6 receptor (R) and IL6 serum levels are associated with enhanced PCa migratory, invasive, clonogenic and metastatic ability. Inhibiting the STAT3 pathway at different levels (cytokines, receptors, and kinases) exhibits relative success in cancer. The present study investigated the effect of Stattic (Stt) + Tocilizumab (Tcz) on proliferative, clonogenic, migratory and invasive ability of human metastatic PCa (assessed by colony formation, wound healing and migration assay). RWPE1 (epithelial prostate immortalized cells), 22Rv1 (Tumor cells), LNCaP (Metastatic cells) and DU145 (metastatic, castrationresistant prostate cells) cells were used in vitro to evaluate levels of cytokines, chemokines, growth factors (Cytometric Bead Array), STAT3, phosphorylated STAT3 (InCell Western), IL6R, vimentin and epithelial (E) cadherin (Western Blot). The effect of inhibition of STAT3 (expressed constitutively in DU145 cells) with Stt and/or Tcz on expression levels of vimentin, VEGF, and Ecadherin, as well as proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells was assessed. The expression levels of IL6, CXC chemokine ligand 8, VEGF and vimentin, as well as proliferation and migration, were increased in metastatic PCa cells. Treatment with Stt or Tcz decreased vimentin and VEGF and increased Ecadherin expression levels and inhibited proliferative, clonogenic, migratory and invasive capacity of DU145 cells; addition of IL6 decreased this inhibitory effect. However, Stt + Tcz maintained inhibition even in the present of high concentrations of IL6. Stt + Tcz decreased expression of vimentin and VEGF and inhibited the proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells. To the best of our knowledge, the present study is the first to combine Stt, a STAT3 inhibitor, with Tcz, an antibody against IL6R, to target tumor cells.