Pluripontency Genes SOX2, c-myc and KLF4 as Potential Therapeutic Targets for Metastasis in Prostate Cancer.

Prostate cancer (PCa) is a main cause oncology mortality in men wide world. Recurrence, castration-resistance and metastasis are the major issues. It has been shown that cancer stem cells (CSCs) are tightly related with to these processes. A core of pluripotency genes have been described in maintaining stemness cell phenotype. Knocking down those stemness may reverse CSCs features making them more sensitive to treatments. The purpose of this study is to evaluate the effect of knocking down of stemness genes on functional characteristics and metastatic capacity of CSCs in PCa.

PCa cell cultures were obtained from several passages primary cultures derived from tumor samples. All protocols were approved by institutional Ethical Committees. Cells were cultured under non-adherent conditions favoring CSCs spheres formation. Pluripotency genes SOX2, KLF4 and c-MYC were knocked down using specific shRNAs within lentiviral vectors. The effects of gene silencing on apoptosis, drug resistance, clonogenic and invasion were analyzed. In addition, metastasis ability of SOX2-knocked down CSCs was assayed in a orthotopic NOD/SCID mice model for human PCa.

Prostate spheres were enriched in CSCs with stem features. Silencing of SOX2, KLF4 and c-MYC reached more than 50% of inhibition. CSCs knocked down for these genes showed chemotherapeutic drugs sensitization, increased apoptotic rate and decreased clonogenic and invasive abilities. SOX2-knocked down CSCs decreased tumor growth rate and completely inhibited metastasis in a orthotopic NOD/SCID model for PCa. The pluripotency genes analyzed have a relevant role in maintaining the stemness functional signature of CSCs from PCa, promoting anti-apoptotic, invasive, resistance, clonogenic, tumorigenic and metastatic characteristics. SOX2 seems to have a determinant role in metastatic progression and might be considered as a suitable therapeutic target for PCa.

Funding: Projects Fondecyt 1140417 (EAC) and 1151214 (HRC).