TCTP as a therapeutic target in melanoma treatment

Translationally controlled tumour protein (TCTP) initially named Q23, P21, and P23, according to its molecular mass, is involved in regulating fundamental cellular processes and is overexpressed in several tumour types (Chung et al, 2000; Amson et al, 2013). Since its characterisation, TCTP has been related to tumourigenesis and cancer progression (Koziol and Gurdon, 2012). Numerous studies show that TCTP level in tumour is higher than that in the corresponding normal tissues, including prostate, renal, breast, and lung cancers (Amson et al, 2013; Acunzo et al, 2014; Ambrosio et al, 2015; Rocca et al, 2015). These observations point to TCTP’s critical role in tumourigenesis and highlight its putative role as a therapeutic target in several cancers. Silencing TCTP was shown to induce tumour reversion, a process overriding the malignant process at the molecular level (Tuynder et al, 2002, 2004; Telerman and Amson, 2009). The decrease of TCTP levels were related to inhibition of tumour growth and the loss of tumour features (high levels cell proliferation and migration) (Amson et al, 2013; Acunzo et al, 2014). Sertraline was first investigated in the context of TCTP and tumours because of the similarity of its structure to antihistaminic compounds; because TCTP encodes for a histamine-releasing factor, the hypothesis that inhibitors of the histaminic pathway could be effective against tumour cells was evaluated. Several articles had already shown that sertraline inhibits tumour growth in vivo (Tuynder et al, 2004). There are epidemiologic studies showing a protective effect and a decreased risk of tumour development (in breast, colorectal, lung cancers) among users of high doses of selective serotonin reuptake inhibitors, including sertraline (Xu et al, 2006; Coogan et al, 2009; Toh et al, 2009; Wernli et al, 2009). There is a negative feedback loop between TCTP and P53. Translationally controlled tumour protein promotes P53 degradation, inhibits MDM2 autoubiquitination, promotes MDM2-mediated ubiquitination, and degradation of P53. Additionally, P53 directly represses TCTP transcription (Amson et al, 2012). In this context sertraline binds directly to TCTP (Amson et al, 2013). The effects of decreasing TCTP in melanoma were analysed using both sertraline and siRNA. In vivo analysis was performed using a C57BL/6 mice model and compared with the alkylating agent dacarbazine (DTIC). Although DTIC is a long-established and standard treatment for metastatic melanoma, its efficiency is low (Pretto and Neri, 2013). The results reported here provide a basis for the evaluation of TCTP targeting in melanoma and suggests sertraline as a potential drug.