TCTP/tpt1 - Remodeling Signaling from Stem Cell to Disease

Ean-Jeong Seo, Nicolas Fischer, Thomas Efferth

The translationally controlled tumor protein (TCTP) is a highly conserved protein that is regulated due to a high number of extracellular stimuli. TCTP has an important role for cell cycle and normal development. On the other side, tumor reversion and malignant transformation have been associated with TCTP. TCTP has been found among the 12 genes that are differentially expressed during mouse oocyte maturation, and an overexpression of this gene was reported in a wide variety of different cancer types. Its antiapoptotic effect is indicated by the interaction with several proapoptotic proteins of the Bcl-2 family and the p53 tumor suppressor protein. In this article, we draw attention to the role of TCTP in cancer, especially, focusing on cell differentiation and tumor reversion, a biological process by which highly tumorigenic cells lose their malignant phenotype. This protein has been shown to be the most strongly downregulated protein in revertant cells compared to the parental cancer cells. Decreased expression of TCTP results either in the reprogramming of cancer cells into reversion or apoptosis. As conventional chemotherapy is frequently associated with the development of drug resistance and high toxicity, the urge for the development of new or additional scientific approaches falls into place. Differentiation therapy aims at reinducing differentiation backward to the nonmalignant cellular state. Here, different approaches have been reported such as the induction of retinoid pathways and the use of histone deacetylase inhibitors. Also, PPARγ agonists and the activation of the vitamin D receptor have been reported as potential targets in differentiation therapy. As TCTP is known as the histamine-releasing factor, antihistaminic drugs have been shown to target this protein. Antihistaminic compounds, hydroxyzine and promethazine, inhibited cell growth of cancer cells and decreased TCTP expression of breast cancer and leukemia cells. Recently, we found that two antihistaminics, levomepromazine and buclizine, inhibited cancer cell growth by direct binding to TCTP and induction of cell differentiation. These data confirmed that TCTP is an exquisite target for anticancer differentiation therapy and antihistaminics have potential to be lead compounds for the direct interaction with TCTP as new inhibitors of human TCTP and tumor growth.