Combination of phospholipase Cε 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.