GLİOBLASTOMA HÜCRE HATLARINDA MPTP MUAMELESİNİN VE MONOAMİN OKSİDAZ B’NİN İFADE SEVİYELERİNİN ARAŞTIRILMASI

Giriş: Glioblastomalar,glia hücrelerinden farklılaşan en agresif ve yaygın tümörlerdir. Yoğun çalışmalara rağmen tatmin edici bir tedavi yöntemi henüz yoktur. Parkinson Hastalığı (PH) ikinci en yaygın nörodejeneratif hastalıktır ve tedavisi yoktur. Var olan tedaviler ancak belli bir noktaya kadar yardımcıdır. Beyin tümörleri ve PH arasındaki ilişki tartışmalıdır. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) güvenilir ve tekrar edilebilir bir PH kimyasal modelidir. Glia hücrelerinde ifade edilen Monoamine Oxidase B (MAO-B) enzimleri, MPTP’yi $MPP^+$(1- Methyl-4-phenylpyridinium)’ye dönüştürür. $MPP^+$ , Complex 1’I inhibe eder ve hücre ölümünü tetikler. MPTP’ nin etkisinive MAO-B enziminin protein ifade seviyelerini glioblastoma hücrelerinde araştırmak önemli olacaktır. Gereç ve Yöntem: MPTP’ninglioblastoma hücrelerinin (A172 ve U87) canlılığı üzerine etkisi MTT assay ile analiz edilmiş ve kontrol glia hücreleri (IHA-immortalize insan astrositleri) ile karşılaştırılmıştır. MAO-B’nin protein ifade seviyeleri de ELISA assay kullanarak glioblastoma hücrelerinde ölçülmüş ve kontrol glia hücreleri ile karşılaştırılmıştır. Bulgular: MPTP muamelesinden sonra, hücre sağkalımı, glioblastoma hücrelerinde kontrol glia hücrelerine göre istatiksel olarak anlamlı bir şekilde daha fazladır. MAO-B protein ifade seviyeleri de glioblastoma hücrelerinde kontrole göre istatiksel olarak anlamlı bir şekilde düşük bulunmuştur. Sonuç: Glioblastoma hücrelerinin, MPTP muamelesine, kontrol glia hücrelerine göre daha dirençli olmalarının nedeninin MAO-B enzimini daha az seviyede ifade etmeleri olduğu düşünülmüştür. Bu neden MAO-B ile ilgili yolakların çalışılması beyin tümörlerine tedavi geliştirilmesi için önemli olacaktır.

THE INVESTIGATION OF THE MPTP TREATMENT AND THE MONOAMINE OXIDASE B EXPRESSION LEVELS IN GLIOBLASTOMA CELL LINES

Introduction:Glioblastomas are the most common and aggressive brain tumors derived from glia cells. Despiteintense studies, unfortunately a satisfactory cure regimen is not available. Parkinson’s Disease (PD) is the secondmost common neurodegenerative disorder without a major cure. Existing therapies are helpful only to a certainpoint. The association between brain tumors and PD remains controversial.MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a reliable and reproducible chemical model for PD. Monoamine Oxidase B (MAO-B)enzymes, expressed by glia cells, convert MPTP to $MPP^+$ (1-Methyl-4-phenylpyridinium) which inhibits Complex Iand induces cell death. It is important to investigate the effect of MPTP and also analyze the protein expressionlevels of MAO-B in glioblastoma cell lines and compare with control glia cells.Materials and Methods: The effect of MPTP on the viability of glioblastoma cell lines (A172 and U87) wasinvestigated using MTT assay and compared with control glia cells(IHA-immortalized human astrocytes). Thelevel of protein expression of Monoamine Oxidase B (MAO-B) was also analyzed in glioblastoma cell lines andcompared with control glia cells using ELISA assay.Results: The cell viability wassignificantly increased in glioblastoma cells when compared to glia cells after MPTPadministration. The protein expression levels of MAO-B are significantly lower in glioblastoma cells compared tocontrol glia cells.Conclusion: Glioblastoma cells might be resistant against MPTP treatment due to having expressed loweramount of MAO-B enzyme so that it will be interesting in the future to investigate the MAO-B-related pathwaysand design therapeutics accordingly for brain tumors.

PDF

___

1. Ohgaki H , Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res 2013; 19(4):764-72.
2. Kiseleva LN, Kartashev AV, Vartanyan NL, Pinevich AA, Samoilovich MP. A172 and T98G Cell Lines Characteristics. Cell and Tissue Biology 2016;10 (5): 341–8.
3. Dauer W, Przedborski S. Parkinson’s Disease: Mechanisms and Models. Neuron 2003; 39: 889–909
4. Klein C, Westenberger A. Genetics of Parkinson’s Disease. Cold Spring Harb Perspect Med. 2012; 2(1): a008888.
5. Gaweska H, Fitzpatrick PF. Structures and mechanism of the monoamine oxidase family. Biomol Concepts 2011; 2(5): 365– 77.
6. Smeyne RJ, Jackson-Lewis V. The MPTP model of Parkinson’s disease. Mol Brain Res. 2005; 134(1): 57-66.
7. Jankovic J. Parkinson’s Disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008; 79: 368-76.
8. Kalia LV, Lang AE. Parkinson’s Disease. Lancet 2015; 386(9996): 896-912.
9. Ye R, Shen T, Jiang Y, Xu L, Si X, Zhang B. The relationship between Parkinson Disease and brain tumor: a meta-analysis. PLoS One. 2016; 11(10): e0164388.
10. Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I et al. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 2010 ; 42(1):77-82.
11. Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012; 483(7390): 479-83.
12. Sharpe MA, Baskin DS. Monoamine oxidase B levels are highly expressed in human gliomas and are correlated with the expression of HiF-1α and with transcription factors Sp1 and Sp3. Oncotarget 2016; 7(3): 3379–93.
13. Park JH, Ju YH, Choi JW, Song HJ, Jang BK, Woo J et al. Newly developed reversible MAO-B inhibitor circumvents the shortcomings of irreversible inhibitors in Alzheimer's disease. Sci Adv 2019; 5(3): eaav0316
14. Feng, DD, Cai W, Chen X. The associations between Parkinson’s disease and cancer: the plot thickens. Transl Neurodegener 2015; 4: 20.