Abstract
LTF (lactotransferrin, also known as lactoferrin) is a key component of innate immune defense. It has recently been found to have anti-tumor and anti-metastatic activity in different cancers. We previously reported LTF to be the most significantly downregulated gene in nasopharyngeal carcinoma (NPC) specimens relative to normal nasopharyngeal epithelial tissues, and it was also negatively associated with the progression and metastasis of NPC. However, the mechanism underlying this remains unclear. In the current study, we revealed that LTF can suppress 3-phosphoinositide-dependent protein kinase 1 expression via the mitogen-activated protein kinase/c-Jun pathway and thus repress AKT signaling. We also showed that LTF interacts with keratin 18 (K18) and so blocks the formation of the K18–14-3-3 complex, leading to downregulation of K18-mediated AKT activation. Thus, LTF suppresses AKT signaling by two separate mechanisms, leading to inhibition of NPC tumorigenesis. This is the first report on the tumor suppressive effects of LTF through repression of AKT signaling in NPC. It suggests that both LTF and AKT signaling merit further study in the field of NPC research.
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References
Montreuil J, Tonnelat J, Mullet S . Preparation and properties of lactosiderophilin (lactotransferrin) of human milk. Biochim Biophys Acta 1960; 45: 413–421.
Ward PP, Paz E, Conneely OM . Multifunctional roles of lactoferrin: a critical overview. Cell Mol Life Sci 2005; 62: 2540–2548.
Gonzalez-Chavez SA, Arevalo-Gallegos S, Rascon-Cruz Q . Lactoferrin: structure, function and applications. Int J Antimicrob Agents 2009; 33: e1–e8.
Sekine K, Watanabe E, Nakamura J, Takasuka N, Kim DJ, Asamoto M et al. Inhibition of azoxymethane-initiated colon tumor by bovine lactoferrin administration in F344 rats. Jpn J Cancer Res 1997; 88: 523–526.
Tsuda H, Sekine K, Nakamura J, Ushida Y, Kuhara T, Takasuka N et al. Inhibition of azoxymethane initiated colon tumor and aberrant crypt foci development by bovine lactoferrin administration in F344 rats. Adv Exp Med Biol 1998; 443: 273–284.
Matsuda Y, Saoo K, Hosokawa K, Yamakawa K, Yokohira M, Zeng Y et al. Post-initiation chemopreventive effects of dietary bovine lactoferrin on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone -induced lung tumorigenesis in female A/J mice. Cancer Lett 2007; 246: 41–46.
Varadhachary A, Wolf JS, Petrak K, O’Malley BW, Spadaro M, Curcio C et al. Oral lactoferrin inhibits growth of established tumors and potentiates conventional chemotherapy. Int J Cancer 2004; 111: 398–403.
Bezault J, Bhimani R, Wiprovnick J, Furmanski P . Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice. Cancer Res 1994; 54: 2310–2312.
Li WY, Li QW, Han ZS, Jiang ZL, Yang H, Li J et al. Growth suppression effects of recombinant adenovirus expressing human lactoferrin on cervical cancer in vitro and in vivo. Cancer Biother Radiopharm 2011; 26: 477–483.
Yi HM, Li H, Peng D, Zhang HJ, Wang L, Zhao M et al. Genetic and epigenetic alterations of LTF at 3p21.3 in nasopharyngeal carcinoma. Oncol Res 2006; 16: 261–272.
Campbell T, Skilton RA, Coombes RC, Shousha S, Graham MD, Luqmani YA . Isolation of a lactoferrin cDNA clone and its expression in human breast cancer. Br J Cancer 1992; 65: 19–26.
Kholodnyuk ID, Kozireva S, Kost-Alimova M, Kashuba V, Klein G, Imreh S . Down regulation of 3p genes, LTF, SLC38A3 and DRR1, upon growth of human chromosome 3-mouse fibrosarcoma hybrids in severe combined immunodeficiency mice. Int J Cancer 2006; 119: 99–107.
Yang Y, Li J, Szeles A, Imreh MP, Kost-Alimova M, Kiss H et al. Consistent downregulation of human lactoferrin gene, in the common eliminated region 1 on 3p21.3, following tumor growth in severe combined immunodeficient (SCID) mice. Cancer Lett 2003; 191: 155–164.
Xiao Y, Monitto CL, Minhas KM, Sidransky D . Lactoferrin down-regulates G1 cyclin-dependent kinases during growth arrest of head and neck cancer cells. Clin Cancer Res 2004; 10: 8683–8686.
Damiens E, El Yazidi I, Mazurier J, Duthille I, Spik G, Boilly-Marer Y . Lactoferrin inhibits G1 cyclin-dependent kinases during growth arrest of human breast carcinoma cells. J Cell Biochem 1999; 74: 486–498.
Son HJ, Lee SH, Choi SY . Human lactoferrin controls the level of retinoblastoma protein and its activity. Biochem Cell Biol 2006; 84: 345–350.
Wu M, Li X, Li G . Signaling transduction network mediated by tumor suppressor/susceptibility genes in NPC. Curr Genomics 2009; 10: 216–222.
Zhou Y, Zeng Z, Zhang W, Xiong W, Wu M, Tan Y et al. Lactotransferrin: a candidate tumor suppressor-deficient expression in human nasopharyngeal carcinoma and inhibition of NPC cell proliferation by modulating the mitogen-activated protein kinase pathway. Int J Cancer 2008; 123: 2065–2072.
Kikani CK, Dong LQ, Liu F . ‘New’-clear functions of PDK1: beyond a master kinase in the cytosol? J Cell Biochem 2005; 96: 1157–1162.
Bayascas JR . Dissecting the role of the 3-phosphoinositide-dependent protein kinase-1 (PDK1) signalling pathways. Cell Cycle 2008; 7: 2978–2982.
Mariller C, Benaissa M, Hardiville S, Breton M, Pradelle G, Mazurier J et al. Human delta-lactoferrin is a transcription factor that enhances Skp1 (S-phase kinase-associated protein) gene expression. FEBS J 2007; 274: 2038–2053.
Lopez-Bergami P, Kim H, Dewing A, Goydos J, Aaronson S, Ronai Z . c-Jun regulates phosphoinositide-dependent kinase 1 transcription: implication for Akt and protein kinase C activities and melanoma tumorigenesis. J Biol Chem 2010; 285: 903–913.
Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7: 261–269.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098–1101.
Wick MJ, Dong LQ, Riojas RA, Ramos FJ, Liu F . Mechanism of phosphorylation of protein kinase B/Akt by a constitutively active 3-phosphoinositide-dependent protein kinase-1. J Biol Chem 2000; 275: 40400–40406.
Omary MB, Ku NO, Strnad P, Hanada S . Toward unraveling the complexity of simple epithelial keratins in human disease. J Clin Invest 2009; 119: 1794–1805.
Trask DK, Band V, Zajchowski DA, Yaswen P, Suh T, Sager R . Keratins as markers that distinguish normal and tumor-derived mammary epithelial cells. Proc Natl Acad Sci USA 1990; 87: 2319–2323.
Kim S, Wong P, Coulombe PA . A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature 2006; 441: 362–365.
Liao J, Omary MB . 14-3-3 proteins associate with phosphorylated simple epithelial keratins during cell cycle progression and act as a solubility cofactor. J Cell Biol 1996; 133: 345–357.
Ku NO, Michie S, Resurreccion EZ, Broome RL, Omary MB . Keratin binding to 14-3-3 proteins modulates keratin filaments and hepatocyte mitotic progression. Proc Natl Acad Sci USA 2002; 99: 4373–4378.
Ku NO, Liao J, Omary MB . Phosphorylation of human keratin 18 serine 33 regulates binding to 14-3-3 proteins. EMBO J 1998; 17: 1892–1906.
Fan SQ, Ma J, Zhou J, Xiong W, Xiao BY, Zhang WL et al. Differential expression of Epstein-Barr virus-encoded RNA and several tumor-related genes in various types of nasopharyngeal epithelial lesions and nasopharyngeal carcinoma using tissue microarray analysis. Hum Pathol 2006; 37: 593–605.
Rodrigues L, Teixeira J, Schmitt F, Paulsson M, Mansson HL . Lactoferrin and cancer disease prevention. Crit Rev Food Sci Nutr 2009; 49: 203–217.
Altomare DA, Testa JR . Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005; 24: 7455–7464.
Testa JR, Tsichlis PN . AKT signaling in normal and malignant cells. Oncogene 2005; 24: 7391–7393.
Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H et al. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci 2003; 94: 851–857.
Zhang DH, Tai LK, Wong LL, Sethi SK, Koay ES . Proteomics of breast cancer: enhanced expression of cytokeratin19 in human epidermal growth factor receptor type 2 positive breast tumors. Proteomics 2005; 5: 1797–1805.
Kippenberger S, Hofmann M, Zoller N, Thaci D, Muller J, Kaufmann R et al. Ligation of beta4 integrins activates PKB/Akt and ERK1/2 by distinct pathways-relevance of the keratin filament. Biochim Biophys Acta 2010; 1803: 940–950.
Eriksson JE, Dechat T, Grin B, Helfand B, Mendez M, Pallari HM et al. Introducing intermediate filaments: from discovery to disease. J Clin Invest 2009; 119: 1763–1771.
Morrison DK . The 14-3-3 proteins: integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell Biol 2009; 19: 16–23.
Obsilova V, Silhan J, Boura E, Teisinger J, Obsil T . 14-3-3 proteins: a family of versatile molecular regulators. Physiol Res 2008; 57: S11–S21.
Darling DL, Yingling J, Wynshaw-Boris A . Role of 14-3-3 proteins in eukaryotic signaling and development. Curr Top Dev Biol 2005; 68: 281–315.
Shaheduzzaman S, Vishwanath A, Furusato B, Cullen J, Chen Y, Bañez L et al. Silencing of Lactotransferrin expression by methylation in prostate cancer progression. Cancer Biol Ther 2007; 6: 1088–1095.
Deng M, Tang H, Zhou Y, Zhou M, Xiong W, Zheng Y et al. miR-216b suppresses tumor growth and invasion by targeting KRAS in nasopharyngeal carcinoma. J Cell Sci 2011; 124: 2997–3005.
Acknowledgements
This work was supported by the China 111 Project (No. 111-2-12), Nature Scientific Foundation of China (30871282, 81071756, 81171988). Ministry of Education (NCET-11-0520, SRF for ROCS). Hunan Province Natural Sciences Foundation of China (10JJ7003).
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Deng, M., Zhang, W., Tang, H. et al. Lactotransferrin acts as a tumor suppressor in nasopharyngeal carcinoma by repressing AKT through multiple mechanisms. Oncogene 32, 4273–4283 (2013). https://doi.org/10.1038/onc.2012.434
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DOI: https://doi.org/10.1038/onc.2012.434
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