Overexpression of Glutathione S-transferase P1 Inhibits the Viability and Motility of Prostate Cancer via Targeting MYC and Inactivating the MEK/ERK1/2 Pathways.

Abstract

Prostate cancer (PC) is one of the most common malignancies of men. Glutathione S-transferase P1 (GSTP1) has been suggested to play a protective role in the prostate. The proto-oncogene MYC has been extensively proved to be a key regulator of tumor transformation from early stage to malignant. Our study aims to investigate the mechanism of GSTP1 in the biological behavior of PC. Compared with normal prostate tissues, the expression of GSTP1 was decreased in PC tissues. Conversely, the level of MYC was increased in PC tissues compared with normal tissues. MYC was convinced a direct target of GSTP1. Besides, the overexpression of GSTP1 or MYC siRNA strongly reduced cell viability via decreasing the volume of cell spheres and cell proliferation rate. GSTP1 overexpression or MYC siRNA also decreased cell motility of PC via reducing the closing rate of scratch wounds and the number of invasive cells. We further explored the underlying mechanism, and found that the level of p-MEK and p-ERK1/2 was strongly decreased in PC3 cells with pcDNA-GSTP1 or MYC siRNA transfection compared with control group. The inhibitory effect on cell viability, p-MEK and p-ERK1/2 was stronger when pcDNA-GSTP1 and MYC siRNA function together. Finally, the in vivo experiment displayed that pcDNA-GSTP1 transfection reduced tumor growth and tumor volume in PC xenografts. The decreased level of metastasis-related proteins VEGF (vascular endothelial growth factor) and MMP (metal matrix proteinase)-9 in GSTP1 overexpression model mice was detected by immunohistochemistry. Besides, the expression of MYC, p-MEK and p-ERK1/2 was strongly inhibited in mice with pcDNA-GSTP1 transfection. Taken together, our research indicates that GSTP1 overexpression inhibits the viability and motility of PC in vitro and in vivo, and may through targeting MYC and inactivating MEK/ERK1/2 pathway.