Translationally Controlled Tumor Protein is a Novel Biological Target for Neurofibromatosis Type 1 (NF1)-associated Tumors [Cell Biology]

August 4th, 2014 by Kobayashi, D., Hirayama, M., Komohara, Y., Mizuguchi, S., Wilson Morifuji, M., Ihn, H., Takeya, M., Kuramochi, A., Araki, N.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that predisposes individuals to develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). Due to the lack of information on the molecular mechanism of NF1-associated tumor pathogenesis or biomarkers/therapeutic targets, an effective treatment for NF1 tumors has not been established. In this study, the novel NF1-associated protein, translationally controlled tumor protein (TCTP), was identified by integrated proteomics and found to be upregulated via activated MAPK/PI3K-AKT signaling in response to growth factors in NF1-deficient Schwann cells. Immunohistochemical analysis of NF1-associated tumors revealed that the TCTP expression level correlated with tumorigenicity. In NF1-deficient MPNST cells, TCTP protein but not mRNA was downregulated by NF1 GTPase-activating protein (GAP)-related domain (GRD) or MAPK/PI3K inhibitors, and this correlated with suppression of mTOR signaling. mTOR inhibition by rapamycin also downregulated TCTP protein expression, while knockdown or overexpression of TCTP suppressed or activated mTOR signaling, respectively, and affected cell viability. These results suggest that a positive feedback loop between TCTP and mTOR contributes to NF1-associated tumor formation. Lastly, the anti-tumor effect of artesunate, which binds to and degrades TCTP, was evaluated. Artesunate significantly suppressed the viability of MPNST cells but not normal Schwann cells, and the TCTP level inversely correlated with artesunate sensitivity. Moreover, combinational use of artesunate and rapamycin enhanced the cytotoxic effect on MPNST cells. These findings suggest that TCTP is functionally implicated in the progression of NF1-associated tumors, and could serve as a biological target for their therapy.