Tumor Suppressive Maspin-Sensitized Prostate Cancer to Drug Treatment Through Negative Regulating Androgen Receptor Expression

Abstract

Overactivation of androgen receptor (AR)-mediated signal has been extensively implicated in prostate cancer (CaP) development, progression, and recurrence, which makes it an attractive therapeutic target. Meanwhile, as an endogenous inhibitor of histone deacetylase 1 (HDAC 1), tumor-suppressive mammary serine protease inhibitor (maspin) was reported to sensitize drug-induced apoptosis with a better therapeutic outcome in CaP, but the relationship between AR and maspin remains unclear. In the current study, treatment of 5-Aza or MS-275/enzalutamide induced poly (ADP-ribose) polymerase (PARP) cleavage and p-H2A.X in CaP cells with an increase of maspin expression but a decrease of AR. Then, treatment with protease inhibitor MG132 did not rescue the above drug-induced loss of AR. In addition, modulation of maspin expression by gene recombinant or siRNA technology showed an inverse correlation between expression of maspin and AR, consequently affecting the AR-regulated downstream gene transcription (e.g., NKX3.1 and TMPRSS2). Bioinformatics analysis of the data extracted from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) database also revealed an inverse correlation between low maspin expression and high AR level in advanced CaP. Furthermore, chromatin immunoprecipitation (ChIP) assay using anti-maspin antibody identified that a portion of AR promoter sequence was co-precipitated and presented in the immunoprecipitated complex. Finally, maspin-mediated repression of AR was induced by treatment of MS-275, which promoted enzalutamide treatment efficacy with decrease of prostate-specific antigen (PSA) expression in LNCaP and 22RV1 cells. Taken together, the data not only demonstrated maspin-mediated repression of AR to augment drug anti-tumor activity but also provided in-depth support for combination of HDAC inhibitors with AR antagonist in CaP therapy.

The Differential Antitumor Activity of 5-Aza-2'-deoxycytidine in Prostate Cancer DU145, 22RV1, and LNCaP Cells

“…To clarify our previous finding of 5-Aza exerting differential cytotoxicity 30 , the three CaP cell lines and RWPE-1 cells were treated with different concentrations of the agent for 96 h, followed by western blotting analysis for the expression of phospho-H2A.X (p-H2A.X) and PARP cleavage. The findings revealed that the levels of p-H2A.X protein were significantly and differentially increased after treatment of DU145, 22RV1, LNCaP cells and RWPE-1 cells with variant doses of 5-Aza (Figure 3 ), suggesting the presence of treatment-induced double strand DNA damage.…”

“…Thus, collectively, the data suggested that the 5-Aza-induced differential cell cycle process in malignant cells was closely associated with the genetic and epigenetic heterogeneity of cancer. Since 5-Aza treatment showed modest inhibitory activities on CaP cells with certain degree of side effects on normal RWPE-1 cells, a better and selective treatment effects of 5-Aza on CaP could be expected if it was implemented in combination with other agents 30 , 32 .…”

“…Clinical data of p53 and p21 expression in CaP tissues were extracted from NCBI GEO profiles datasets and were analyzed as described previously 30 . All the experiments were repeated in triplicate.…”

Identification and Exploration of Novel Macrophage M2-Related Biomarkers and Potential Therapeutic Agents in Endometriosis

“…Therefore, it can be used in the treatment of inflammation and cancers ( Lee et al, 2012 ). MS-27 is an HDAC inhibitor and cell cycle inhibitor that has also shown potent antitumor activity ( Tang et al, 2020 ). Cancer cells can develop resistance to multiple therapeutic drugs, which is the major challenge for the effective treatment of cancer patients.…”

Bacterial Lipopolysaccharide Augmented Malignant Transformation and Promoted the Stemness in Prostate Cancer Epithelial Cells

“…22,41,43 Our studies also showed that inhibition of HDAC activity by TSA or other HDAC inhibitors reversed EMT and attenuated the processing of cell invasion and migration. 29,44,45 However, the opposite effects of TSA on promoting cell transformation and proliferation were also observed. For instance, PCa cells developed resistance to TSA.…”