Translationally controlled tumour protein TCTP is induced early in human colorectal tumours and contributes to the resistance of HCT116 colon cancer cells to 5-FU and oxaliplatin

Abstract

BackgroundTranslationally controlled tumour protein TCTP is an anti-apoptotic protein frequently overexpressed in cancers, where high levels are often associated with poor patient outcome. TCTP may be involved in protecting cancer cells against the cytotoxic action of anti-cancer drugs. Here we study the early increase of TCTP levels in human colorectal cancer (CRC) and the regulation of TCTP expression in HCT116 colon cancer cells, in response to treatment with the anti-cancer drugs 5-FU and oxaliplatin.MethodsUsing immunohistochemistry, we assessed TCTP levels in surgical samples from adenomas and adenocarcinomas of the colon, compared to normal colon tissue. We also studied the regulation of TCTP in HCT116 colon cancer cells in response to 5-FU and oxaliplatin by western blotting. TCTP mRNA levels were assessed by RT-qPCR. We used mTOR kinase inhibitors to demonstrate mTOR-dependent translational regulation of TCTP under these conditions. Employing the Real-Time Cell Analysis (RTCA) System and the MTS assay, we investigated the effect of TCTP-knockdown on the sensitivity of HCT116 cells to the anti-cancer drugs 5-FU and oxaliplatin.Results1. TCTP levels are significantly increased in colon adenomas and adenocarcinomas, compared to normal colon tissue. 2. TCTP protein levels are about 4-fold upregulated in HCT116 colon cancer cells, in response to 5-FU and oxaliplatin treatment, whereas TCTP mRNA levels are down regulated. 3. mTOR kinase inhibitors prevented the up-regulation of TCTP protein, indicating that TCTP is translationally regulated through the mTOR complex 1 signalling pathway under these conditions. 4. Using two cellular assay systems, we demonstrated that TCTP-knockdown sensitises HCT116 cells to the cytotoxicity caused by 5-FU and oxaliplatin.ConclusionsOur results demonstrate that TCTP levels increase significantly in the early stages of CRC development. In colon cancer cells, expression of this protein is largely upregulated during treatment with the DNA-damaging anti-cancer drugs 5-FU and oxaliplatin, as part of the cellular stress response. TCTP may thus contribute to the development of anti-cancer drug resistance. These findings indicate that TCTP might be suitable as a biomarker and that combinatorial treatment using 5-FU/oxaliplatin, together with mTOR kinase inhibitors, could be a route to preventing the development of resistance to these drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-017-0164-3) contains supplementary material, which is available to authorized users.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…A more recent report on the interaction of Drosophila TCTP confirmed the (genetic) interaction with the ATM kinase and its activation by TCTP (Hong and Choi 2013). These studies demonstrated the importance of TCTP in maintaining genome stability under genotoxic stress, which is consistent with observations from Fujise's and our own laboratory, showing that TCTP is able to protect cancer cells against the cytotoxicity exerted by DNA-damaging anticancer drugs Bommer et al 2017). The involvement of TCTP in the development of chemoresistance in cancer chemotherapy has also been emphasised by several other papers (Jung et al 2014;Takahashi et al 2010;He et al 2015;Sinha et al 2000).…”

“…We have shown that HCT116 colon cancer cells respond to treatment with 5-fluorouracil (5-FU) or with oxaliplatin, two agents frequently used in CRC treatment, with increased TCTP expression. This is probably part of a cellular stress response, since increased TCTP levels protected these cells against the cytotoxicity exerted by these drugs (Bommer et al 2017). Similarly, the contribution of TCTP (HRF) to the development of cell adhesion and chemoresistance was reported in non-Hodgkin lymphomas (He et al 2015).…”

“…Colorectal cancer (CRC) with its distinct morphology of precancerous lesions, such as adenomas, is amenable for such investigations. Recently, we (Bommer et al 2017) and a Chinese group (Xiao et al 2016) demonstrated that indeed TCTP levels (assessed by immunohistochemistry) increase early in CRC, already at the adenoma stage. This is consistent with our finding that during growthinduction of both HeLa cells and HT29 colon cancer cells, TCTP synthesis is translationally up-regulated through the PI3K/Akt/mTORC1 signalling pathway (Bommer et al 2015), given the earlier observation that this pathway is activated early in the development of colorectal cancer (Zhang et al 2009).…”

“…Since the TCTP mRNA also features a 5 0 -TOP (Yamashita et al 2008), we recently revisited this topic and showed that the growth factor-dependent induction of TCTP synthesis is indeed regulated through the PI3K/Akt/mTORC1 pathway and eIF4E (Bommer et al 2015). We also found that treatment of colon cancer cells with DNA-damaging anticancer drugs leads to a four-fold up-regulation of TCTP levels through the mTORC1 pathway (Bommer et al 2017). Similarly, Goodman et al reported an increase in TCTP levels in muscle hypertrophy and atrophy and its regulation through mTOR signalling (Goodman et al 2017).…”

“…the antagonism of TCTP to the tumour suppressor protein p53, which is crucial for TCTP to exert its cancer-promoting activity (Amson et al 2012;Chen et al 2011). The cytoprotective role of TCTP in cancer cells is well documented, for example in conditions of oxidative stress (Lucibello et al 2011), or of treatment with various anticancer drugs, the latter often resulting in chemoresistance of these cells (Li et al 2001;Jung et al 2014;Graidist et al 2004;Bommer et al 2017;He et al 2015), which is a frequent problem in cancer chemotherapy. 2.…”