Ndrg1’in kanser ve demir şelatörleri ile ilişkisi

Abstract

İnsan N-myc downstream-regulated gene1 (Ndrg1), ilk olarak Charcot-Marie-Tooth tip 4D (CMT4D) hastalığında tanımlanmıştır. Son zamanlarda ise hücre diferansiyasyonu, proliferasyon ve büyümenin baskılanması, neoplazi, tümör progresyonu ve metastaz ile ilişkisi ortaya konulmuştur. Ndrg1 geni, farklı kanser türlerinde farklı şekilde etkilenmektedir. Meme, prostat, kolon kanseri gibi kanserlerde downregule iken, karaciğer kanserlerinde upregüle’dir. Ndrg1 geninin düzenlenmesinde farklı hücre tiplerinde farklı ve kompleks mekanizmalar rol alabilmektedir. Bu kompleks düzenlemeler, transkripsiyonel, posttranskripsiyonel ve translasyonal seviyelerdeki major yolları içerir. Yapılan çalışmalarda desferoksamin (DFO) ve diğer şelatörlerin etkili anti-tümör ajanlar oldukları gösterilmiştir. Şelatörler bu etkilerini muhtemelen Ndrg1 mRNA transkripsiyonunu etkileyerek göstermektedir. Ancak bu regülasyonun hangi mekanizma ile oluştuğu net değildir ve demirin gen ekspresyonu ve proliferasyondaki rolünü irdelerken Ndrg1’in daha fazla araştırılması gerekmektedir. Association of Ndrg-1 with cancer and iron chelators Human N-myc downstream-regulated gene 1 (Ndrg-1) has been first identified in Charhot-Marie-Tooth Disease type 4D (CMT4D). Recently, its association with cell differentiation, suppression of growth and proliferation, neoplasia, tumor progression and metastasis has been demonstrated. Ndrg-1 gene appears to be regulated in a variety of ways in different types of cancers. It is down-regulated in breast, prostate and colon cancers whereas it is up-regulated in hepatic cancers. Different and complex mechanisms may play a role in different types of cells in regulation of Ndrg-1 gene. These complex regulations includes major pathways in transcriptional, post-transcriptional and translational levels. It has been shown that desferrioxamine (DFO) and other chelators are effective anti-tumor agents. It’s possible that this effect of chelators is related to Ndrg-1 mRNA transcription, but it remains unknown which mechanism mediates this regulation and iron’s role in gene expression and proliferation and Ndrg-1 need further investigations.

Keywords

• Demir; desferoksamin; diferansiyasyon; HIF-1; kanser; Ndrg-1 (Iron; desferrioxamine; differentiation; HIF-1; cancer; Ndrg-1)

References

1. Andrews, N.C., 1999. Disorders of iron metabolism. New Engl. J. Med. 341, 1986-1995.
2. Ando, T., Ishiguro, H., Kimura, M., Mitsui, A., Kurehara, H., Sugito, N., Tomoda, K., Mori, R., Takashima, N., Ogawa, R., Fujii, Y., Kuwabara, Y., 2006. Decreased expression of NDRG1 is correlated with tumor progression and poor prognosis in patients with esophageal squamous cell carcinoma. Dis. Esophagus. 19, 454-458.
3. Cangul, H., Salnikow, K., Yee, H., Zagzag, D., Commes, T., Costa, M., 2002. Enhanced expression of a novel protein in human cancer cells: A potential aid to cancer diagnosis. Cell Biol. Toxicol. 18, 87-96.
4. Chaston, T.B., Lovejoy, D.B., Watts, R.N., Richardson, D.R., 2003. Examination of the anti-proliferative activity of iron chelators: Multiple cellular targets and the different mechanism of action of Triapine compared with desferrioxamine and the potent pyridoxal isonicotinoyl hydrazone analogue 311. Clin. Cancer Res. 9, 402-414.
5. Chua, M.S., Sun, H., Cheung, S.T., Mason, V., Higgins, J., Ross, D.T., Fan, S.T., So, S., 2007. Overexpression of NDRG1 is an indicator of poor prognosis in hepatocellular carcinoma, Modern Pathol. 20, 76-83.
6. Guan, R.J., Ford, H.L., Fu, Y., Li, Y., Shaw, L.M., Pardee, A.B., 2000. Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res. 60, 749-755.
7. Hershko, C., 1994. Control of disease by selective iron depletion: A novel therapeutic strategy utilizing iron chelators. Baillieres Clin. Haematol. 7, 965-1000. http://atlasgeneticsoncology.org/Genes/NDRG1ID41512ch8q24.html.
8. Inagaki, Y., Tang, W., Xu, HL., Guo, Q., Mafune, K., Konishi, T., Nakata, M., Sugawara, Y., Kokudo, N., 2009. Localization of N-myc downstreamregulated gene 1 in gastric cancer tissue. Digest. Liver Dis. 41, 96-103.

9. Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A. J.M., Asara, J.M., Lane, W.S., Kaelin, W.G., Jr., 2001. HIF alpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science. 292, 464-468.
10. Jaakkola, P., Mole, D.R., Tian, Y.M., Wilson, M.I., Gielbert, J., Gaskell, S.J., Kriegsheim, A., Hebestreit, H.F., Mukherji, M., Schofield, C.J.P.H., Maxwell, P.H., Pugh, C.W., Ratcliffe, P.J., 2001. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 292, 468-472.
11. Jiang, K., Shen, Z., Ye, Y., Yang, X., Wang, S., 2010. A novel molecular marker for early detection and evaluating prognosis of gastric cancer: N-myc downstream regulated gene-1 (NDRG1). Scand. J. Gastroentero. 45, 898-908.
12. Jones, P.A., Taylor, S.M., 1980. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 20, 85-93.
13. Kalaydjieva, L., Gresham, D., Gooding, R., Heather, L., Baas, F., de Jonge, R., Blechschmidt, K., Angelicheva, D., Chandler, D., Worsley, P., Rosenthal, A., King, R.H., Thomas, P.K., 2000. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathyLom. Am. J. Hum. Genet. 67, 47-58.
14. Kalaydjieva, L., Hallmayer, J., Chandler, D., Savov, A., Nikolova, A., Angelicheva, D., King, R.H., Ishpekova, B., Honeyman, K., Calafell, F., Shmarov, A., Petrova, J., Turnev, I., Hristova, A., Moskov, M., Stancheva, S., Petkova, I., Bittles, A.H., Georgieva, V., Middleton, L., Thomas, P.K. 1996. Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nat. Genet. 14, 214-217. Kokame, K., Kato, H., Miyata, T. 1996. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis, J. Biol. Chem. 271, 29659-29665.