Abstract 3928: Sertraline in melanoma treatment: TCTP as a therapeutic target

Abstract

Background: Sertraline (an SSRI antidepressant) binds directly to TCTP protein and decreases its intracellular levels. TCTP (Translationally Controlled Tumor Protein) is an antiapoptotic protein highly conserved through phylogeny. TCTP overexpression was detected in several tumor types. Silencing TCTP was shown to induce tumor reversion, a process overriding at the molecular level the malignant process. There is a reciprocal repression between TCTP and P53. Methods: We evaluated the role of TCTP in melanoma using sertraline and siRNA. Cell viability, migration and clonogenicity were assessed in human and murine melanoma cell in vitro. Sertraline was evaluated in vivo in a murine melanoma model and compared to dacarbazine, a major a chemotherapeutic agent used in melanoma treatment. Long-term effect of sertraline was evaluated keeping cells on regular culture for 5 days after a 72h-treatment and then assessing proliferation, clonogenicity and in vivo growth. Results: (i) In human melanoma cell lines, sertraline treatment and decrease of TCTP levels (by siRNA) are related to the inhibition of clonogenicity and migration; (ii) TCTP levels are related to melanoma malignancy and invasiveness (in B16F10/F1 murine model); (iii) knockdown of TCTP triggers decrease of proliferation and migration on murine melanoma cells; (iv) sertraline decreases TCTP mRNA levels in B16F10 cells and results in inhibition of clonogenicity; (v) sertraline presents remarkable in vivo antitumoral effects in B16F10/C57BL6 model, greater than dacarbazine, the main chemotherapeutic agent used for melanoma; (vi) sertraline treatment is capable of a long-term effect on melanoma cells, suggesting that the drug can trigger tumor reversion, a reprogram of tumor cells to a less malignant phenotype. Our data could pave the way for new approaches in the treatment of melanoma, a pathology whose prognostic is poor in late stages, and the efficiency of the current available chemotherapeutic treatment is very low. Conclusion: Altogether, these results indicate that sertraline could be effective against melanoma and TCTP can be a target for melanoma treatment, opening up new therapies for melanoma treatment. Citation Format: Marianna Boia-Ferreira, Alana Basílio, Antonielle B. Baldissera, Fernando H. Matsubara, Marcia H. Appel, Cleber R. da Costa, Olga M. Chaim, Luiza H. Gremski, Silvio S. Veiga, Andrea Senff-Ribeiro. Sertraline in melanoma treatment: TCTP as a therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3928.