Mechanisms of Cell Death Induced by Histone Deacetylase Inhibitors in Androgen Receptor–Positive Prostate Cancer Cells

Abstract

Histone deacetylase inhibitors (HDACI) are potential therapeutic agents that inhibit tumor cell growth and survival. Although there are several publications regarding the effects of HDACIs on prostate cancer cell growth, their mechanism(s) of action remains undefined. We treated several human prostate cancer cell lines with the HDACI trichostatin A and found that trichostatin A induced cell death in androgen receptor (AR) -positive cell lines to higher extent compared with AR-negative cell lines. We then discovered that trichostatin A and other HDACIs suppressed AR gene expression in prostate cancer cell lines as well as in AR-positive breast carcinoma cells and in mouse prostate. Trichostatin A also induced caspase activation, but trichostatin A -induced AR suppression and cell death were caspase independent. In addition, we found that doxorubicin inhibited AR expression, and p21 protein completely disappeared after simultaneous treatment with trichostatin A and doxorubicin. This effect may be attributed to the induction of protease activity under simultaneous treatment with these two agents. Further, simultaneous treatment with trichostatin A and doxorubicin increased cell death in AR-positive cells even after culturing in steroid-free conditions. The protease/proteasome inhibitor MG132 protected AR and p21 from the effects of trichostatin A and doxorubicin and inhibited trichostatin A -induced cell death in AR-positive prostate cells. Taken together, our data suggest that the main mechanism of trichostatin A -induced cell death in AR-positive prostate cancer is inhibition of AR gene expression. The synergistic effect of simultaneous treatment with trichostatin A and doxorubicin is mediated via inhibition of AR expression, induction of protease activity, increased expression of p53, and proteolysis of p21.

TSA-induced cell death in prostate cancer cell lines is caspase-2 dependent and involves the PIDDosome

“…17 We previously described redistribution of p53 from the cytosol to the Triton X-100-insoluble fraction, which consists of lipid rafts, cytoskeletal proteins, and chromatin in response to TSA treatment in LNCaP. 15 DU145 also demonstrated down regulation of p53 in the cytosol in response to TSA and this down regulation was inhibited in DU145 siCaspase-2 (Taghiyev AF, Guseva NV, Rokhlin OW, Cohen MB. unpublished data).…”

“…At the same time, using a caspase-9 specific inhibitor Z-LEHD-fmk and caspase-9dn expressing DU145 showed an 85% decrease of caspase activity after TSA treatment compared to control. 14,15 It is possible, that caspase-8 initiated caspase cascade occurs via DISC formation due to altered expression of TNF-family receptors and/or ligands. There are several publications indicating upregulation of TNF family receptors and ligands after HDI treatment.…”

“…[12][13][14][15] In addition, the intrinsic mitochondrial pathway is important in the activation of the caspase cascade and overexpression of Bcl-2 downregulates this activation. [12][13][14] The role of caspase-2 in the apoptotic response remains controversial.…”

IFI16 in Human Prostate Cancer

“…Moreover, studies have indicated that inhibitors of HDACs differentially induce apoptosis in prostate cancer cells (13,14). Importantly, treatment of LNCaP cells with trichostatin A (TSA) is shown to induce cell death through downregulation of the transcription of the androgen receptor (AR) gene (14).…”

Effect of histone deacetylase inhibitor on proliferation of biliary tract cancer cell lines

“…Experiments in vitro have shown that TSA can be used in the treatment of ovarian cancer, pancreatic endocrine carcinoma, prostate cancer, etc [16][17][18] . The results of this study focusing on the effect of histone deacetylase inhibitor, trichostatin A (TSA) on the proliferation of gallbladder carcinoma cell line (Mz-ChA-l cell line) and cholangiocarcinoma cell lines (QBC939, KMBC and OZ cell lines) in vivo and in vitro, have demonstrated the value of biotherapy for biliary tract cancer with TSA.…”