Combination of phospholipase C[epsilon] knockdown with GANT61 sensitizes castration-resistant prostate cancer cells to enzalutamide by suppressing the androgen receptor signaling pathway

Castration-resistant prostate cancer (CRPC) is a major challenge in the treatment of prostate cancer (PCa). Phospholipase C[epsilon] (PLC[epsilon]), an oncogene, has been found to be involved in the carcinogenesis, tumor proliferation and migration of several types of cancer. The effects, however, of PLC[epsilon] on CRPC remains unclear. In the present study, the expression of PLC[epsilon] and glioma-associated homolog (Gli)-1/Gli-2 in benign prostatic hyperplasia (BPH), PCa and CRPC tissues and cells was investigated, and the correlations between PLC[epsilon] and Gli-1/Gli-2 in CRPC tissues and cell lines were further explored. In addition, the effect of PLC[epsilon] on cell proliferation and invasion was assessed in CRPC cell lines, and the sensitivity of EN-R and 22RV1 cells to enzalutamide following the downregulation of PLC[epsilon] expression was determined using lentivirus-mediated shPLC[epsilon] and/or treatment with specific Gli inhibitor GANT61. It was found that the PLC[epsilon] expression was excessively upregulated in the majority of CRPC tissues, and PLC[epsilon] positivity was linked to poor progression-free survival (PFS) and overall survival (OS) in patients with PCa. Furthermore, PLC[epsilon] knockdown significantly suppressed CRPC cell proliferation and invasion. Of note, it was found that PLC[epsilon] knockdown increased the sensitivity of CRPC cells to enzalutamide in vitro by suppressing androgen receptor (AR) activities via the non-canonical Hedgehog/Gli-2 and p-STAT3 signaling pathways. PLC[epsilon] knockdown was shown to increase the sensitivity of CRPC cell xenografts to enzalutamide in vivo. Finally, the combination of PLC[epsilon] knockdown with GANT61 significantly sensitized CRPC cells to enzalutamide. Collectively, the results of the present study suggest that PLC[epsilon] is a potential therapeutic target for CRPC.