title: Translationally controlled tumor protein is a novel biological target for neurofibromatosis type 1-associated tumors.
abstract: 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 up-regulated 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 down-regulated by NF1 GTPase-activating protein-related domain or MAPK/PI3K inhibitors, and this correlated with suppression of mammalian target of rapamycin (mTOR) signaling. mTOR inhibition by rapamycin also down-regulated TCTP protein expression, whereas 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. Last, 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.
authors.affiliation: Department of Tumor Genetics and Biology, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Kobayashi
authors.affiliation: Department of Tumor Genetics and Biology, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Mio
authors.initials: M
authors.lastname: Hirayama
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, and Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.affiliation: Department of Tumor Genetics and Biology, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Souhei
authors.initials: S
authors.lastname: Mizuguchi
authors.affiliation: Department of Tumor Genetics and Biology, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Wilson Morifuji
authors.affiliation: Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan and.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Ihn
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, and Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.affiliation: Department of Dermatology, Saitama Medical University, Saitama 350-0495, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kuramochi
authors.affiliation: Department of Tumor Genetics and Biology, Kumamoto University, Kumamoto 860-8556, Japan. Electronic address: nori@gpo.kumamoto-u.ac.jp.
authors.forename: Norie
authors.initials: N
authors.lastname: Araki
mesh_terms: D000818:Animals; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D020932:Nerve Growth Factor / Q000502:physiology; D009456:Neurofibromatosis 1 / Q000378:metabolism* / Q000473:pathology; D025542:Neurofibromin 1 / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D012583:Schwann Cells / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000090324:Tumor Protein, Translationally-Controlled 1; D015854:Up-Regulation
chemical_list: D037621:Artemisinins; D014408:Biomarkers, Tumor; D025542:Neurofibromin 1; C000715647:TPT1 protein, human; C000715648:Tpt1 protein, mouse; C000715649:Tpt1 protein, rat; D000090324:Tumor Protein, Translationally-Controlled 1; D000077332:Artesunate; D020932:Nerve Growth Factor; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Malignant Peripheral Nerve Sheath Tumors (MPNST); Neurofibroma; Neurofibromatosis Type 1 (NF1); Proteomics; Translationally Controlled Tumor Protein (TCTP); Tumor Marker; Tumor Suppressor Gene; Tumor Therapy; mTOR
references.citation: Nature. 2012 May 02;485(7396):109-13
references.pmid: 22552098
references.citation: Mol Cancer Ther. 2011 Dec;10(12):2224-33
references.pmid: 21998290
references.citation: Cancer Res. 2005 Apr 1;65(7):2755-60
references.pmid: 15805275
references.citation: Glia. 2008 Nov 1;56(14):1590-605
references.pmid: 18803326
references.citation: Mol Cell Proteomics. 2013 May;12(5):1377-94
references.pmid: 23358504
references.citation: Genomics. 1987 Dec;1(4):353-7
references.pmid: 2896629
references.citation: Diabetologia. 2012 Apr;55(4):1205-17
references.pmid: 22311416
references.citation: J Pathol. 2009 Apr;217(5):693-701
references.pmid: 19142971
references.citation: Science. 1995 Aug 4;269(5224):688-90
references.pmid: 7542803
references.citation: Mol Biochem Parasitol. 1991 Dec;49(2):181-9
references.pmid: 1775162
references.citation: Arch Pharm Res. 2006 Jan;29(1):50-8
references.pmid: 16491843
references.citation: Int J Biochem Cell Biol. 2004 Mar;36(3):379-85
references.pmid: 14687915
references.citation: J Biol Chem. 2000 Sep 29;275(39):30740-5
references.pmid: 10900196
references.citation: Oncogene. 2004 Apr 19;23(18):3151-71
references.pmid: 15094765
references.citation: Nat Rev Cancer. 2009 Mar;9(3):206-16
references.pmid: 19180095
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):13892-7
references.pmid: 14623968
references.citation: Nature. 2007 Feb 15;445(7129):785-8
references.pmid: 17301792
references.citation: Biochem Int. 1989 Aug;19(2):277-86
references.pmid: 2479380
references.citation: J Biol Chem. 2001 Dec 14;276(50):47542-9
references.pmid: 11598139
references.citation: Oncogene. 2008 Sep 18;27(42):5554-66
references.pmid: 18504434
references.citation: J Biol Chem. 2008 Apr 4;283(14):9399-413
references.pmid: 18218617
references.citation: Int J Cancer. 2010 Sep 1;127(6):1475-85
references.pmid: 20232396
references.citation: Biochim Biophys Acta. 2006 May-Jun;1757(5-6):631-8
references.pmid: 16806052
references.citation: Nature. 2012 Feb 22;485(7396):55-61
references.pmid: 22367541
references.citation: Mol Cell Biol. 2005 Apr;25(8):3117-26
references.pmid: 15798198
references.citation: J Biol Chem. 2003 Jul 18;278(29):26958-69
references.pmid: 12730209
references.citation: Neuropathology. 2003 Mar;23(1):68-78
references.pmid: 12722929
references.citation: Mol Cell Proteomics. 2009 Oct;8(10):2350-67
references.pmid: 19525549
references.citation: Cell. 1990 Jul 13;62(1):193-201
references.pmid: 2114220
references.citation: Trends Biochem Sci. 2006 Jun;31(6):342-8
references.pmid: 16679021
references.citation: Endocrinology. 2014 Feb;155(2):392-404
references.pmid: 24248465
references.citation: Proc Natl Acad Sci U S A. 1982 Oct;79(19):5876-80
references.pmid: 6964392
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14976-81
references.pmid: 12399545
references.citation: Nature. 2002 Jan 31;415(6871):526-30
references.pmid: 11793011
references.citation: J Cell Sci. 1999 Apr;112 ( Pt 8):1257-71
references.pmid: 10085260
references.citation: J Biol Chem. 1998 Jun 26;273(26):16192-8
references.pmid: 9632675
references.citation: Cell Death Differ. 2008 Aug;15(8):1211-20
references.pmid: 18274553
references.citation: Curr Biol. 2008 Jan 8;18(1):56-62
references.pmid: 18164202