Background:Translationally controlled tumour protein (TCTP) is an antiapoptotic protein highly conserved through phylogeny. Translationally controlled tumour protein overexpression was detected in several tumour types. Silencing TCTP was shown to induce tumour reversion. There is a reciprocal repression between TCTP and P53. Sertraline interacts with TCTP and decreases its cellular levels.Methods:We evaluate the role of TCTP in melanoma using sertraline and siRNA. Cell viability, migration, and clonogenicity were assessed in human and murine melanoma cells in vitro. Sertraline was evaluated in a murine melanoma model and was compared with dacarbazine, a major chemotherapeutic agent used in melanoma treatment.Results:Inhibition of TCTP levels decreases melanoma cell viability, migration, clonogenicity, and in vivo tumour growth. Human melanoma cells treated with sertraline show diminished migration properties and capacity to form colonies. Sertraline was effective in inhibiting tumour growth in a murine melanoma model; its effect was stronger when compared with dacarbazine.Conclusions:Altogether, these results indicate that sertraline could be effective against melanoma and TCTP can be a target for melanoma therapy.
LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in Loxosceles brown spider venoms. These proteins are known as histamine-releasing factors (HRF). TCTPs participate in allergic and anaphylactic reactions, which suggest their potential role as therapeutic targets. The histaminergic effect of TCTP is related to its pro-inflammatory functions. An initial characterization of LiTCTP in animal models showed that this toxin can increase the microvascular permeability of skin vessels and induce paw edema in a dose-dependent manner. We evaluated the role of LiTCTP in vitro and in vivo in the inflammatory and allergic aspects that undergo the biological responses observed in Loxoscelism, the clinical condition after an accident with Loxosceles spiders. Our results showed LiTCTP recombinant toxin (LiRecTCTP) as an essential synergistic factor for the dermonecrotic toxin actions (LiRecDT1, known as the main toxin in the pathophysiology of Loxoscelism), revealing its contribution to the exacerbated inflammatory response clinically observed in envenomated patients.
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.
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