Targeting TCTP as a New Therapeutic Strategy in Castration-resistant Prostate Cancer

Abstract

Heat shock protein 27 (Hsp27) is highly overexpressed in castration-resistant prostate cancer (CRPC) and an antisense inhibitor (OGX-427) is currently in phase II clinical trials. In order to understand mechanisms of action of Hsp27 and find new therapeutic targets specific of CRPC, we screened for Hsp27 client proteins. Here, we report that translationally controlled tumor protein (TCTP) is a new Hsp27 client protein involved in Hsp27 cytoprotection. We found that TCTP expression is absent or weak in normal prostate cells, moderately expressed in 18.5% of treatment naive PC, and becomes uniformly and strongly expressed in 75% of CRPC. To define TCTP function, we developed and worldwide patented a TCTP antisense oligonucleotide (ASO). Interestingly, we found that CRPC progression correlates with TCTP overexpression and loss of P53. TCTP knockdown restored P53 expression and function, suggesting that castration-sensitivity is directly linked to P53 expression. Collectively, these findings provide a new Hsp27 cytoprotection mechanism in CRPC, and preclinical proof-of-concept that combining ASO-mediated TCTP knockdown with castration and/or docetaxel therapy could serve as a novel strategy to treat CRPC, with no or little toxicity for normal prostate cells.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…Another example of TCTP being involved in advanced state malignant disease came from a study on prostate cancer (PC). Baylot et al demonstrated that TCTP is particularly expressed in the castration-resistant form of PC and in metastases of the bone, liver and lymph nodes resulting from this (Baylot et al 2012). Their results also show that knockdown of TCTP inhibits growth of prostate cancer cells, progression of castration-resistant tumours in mice and reduces their chemoresistance to docetaxel.…”

“…In their study, they used a mouse model to show that treatment with the TCTP-ASO inhibits tumour growth in castrationresistant prostate cancer, enhances docetaxel chemotherapy and delays cancer progression in vivo. This effect is associated with an increase in P53 levels (Acunzo et al 2014;Baylot et al 2012). In addition, recently a peptide aptamer (WGQWPYHC) targeting TCTP was tested and found to display specific cytotoxicity towards TCTP expressing tumour cells, without affecting normal cells (Kadioglu and Efferth 2016).…”

“…Antisense oligonucleotides (ASOs) and anti-TCTP peptide. Synthetic agents that target TCTP were first used by Baylot and colleagues, who patented an ASO against TCTP (Baylot et al 2012). In their study, they used a mouse model to show that treatment with the TCTP-ASO inhibits tumour growth in castrationresistant prostate cancer, enhances docetaxel chemotherapy and delays cancer progression in vivo.…”

“…There are a few reports, which indicate that in specific instances TCTP protein may be subject to regulated degradation. Two studies described the ability of another anti-apoptotic protein, Mcl-1 (Zhang et al 2002), and heat-shock protein Hsp27 (Baylot et al 2012) to stabilise the TCTP protein, which implies that it may be destabilised if those proteins are absent. Kubiak et al reported that TCTP, a protein involved in maintaining the integrity of the mitotic spindle, is partially degraded during mitotic exit (Kubiak et al 2008).…”

Targeted Efficacy of Dihydroartemisinin for Translationally Controlled Protein Expression in a Lung Cancer Model

“…Many researches show that TCTP level in tumor is higher than that in the corresponding normal tissues, indicating its critical role in tumorigenesis (Amson et al, 2011;Amson et al, 2013). Among 20 screened proteins in lung cancer, TCTP is one of the most overexpressed proteins in human lung cancer cells compared with the normal cells, suggesting that TCTP can be a good biomarker for lung cancer ( Lo et al, 2012;Baylot et al, 2012;Acunzo et al, 2014).…”