Parkinson Hastalığı ve Akciğer Kanserinde PI3K/Akt Yolağı Faktörlerinin Ekspresyon Düzeylerinin Karşılaştırılması

Yıl 2018, Cilt: 8 Sayı: 2, 52 - 57, 12.11.2018

Elif Şanlı Nazlı Yalçınkaya Erdem Tüzün

Öz

DOI: 10.26650/experimed.2018.18003

Amaç: Parkinson hastalığı (PH) kırk yaş
üzeri popülasyonun %0,2’ni etkileyen en sık görülen nörodejeneratif hastalıklardan
biridir. Yapılan çalışmalarla PH’de kanser prevalansının düşük olduğu
gösterilmiştir. Bu sonuçlar sebebiyle fosfoinositidil-3-kinaz (PI3K)/Akt
sağkalım yolağı dikkatleri çekmiştir. Bu yolağa ait gen ekspresyon
değişikliklerinin incelenmesi, PH tedavi ve biyobelirteçlerinin bulunması
amaçlanmıştır.

Gereç ve Yöntem: Çalışmamızda, PH, akciğer
kanseri (AK) hastalarından ve sağlıklı kontrollerden alınan periferik kan
mononükleer hücrelerinde DJ-1-PI3K/Akt sinyal yolağı komponentlerinin ve bu
yolağı etkileyen proteinlerin ekspresyonu ölçülmüş, ekspresyon düzeylerinin
PH’nin klinik parametreleri ile korelasyonu araştırılmıştır.

Bulgular: Fosfataz ve tensin homolog (PTEN)
ve mitokondriyal apoptoz-indükleyici faktör 1 (Aifm1)’in PH’de sağlıklı
kontrollere göre anlamlı derecede azaldığı ve insülin-benzeri büyüme faktörü
(IGF-1)’in anlamlı derecede arttığı saptandı. AK hastalarında ise PTEN,
kaspaz-3 ve α-sinükleinin ekspresyonlarının anlamlı derece arttığı, IGF-1’in
anlamlı derecede azaldığı saptandı. Ayrıca α-sinüklein, IGF-1, kaspaz-3, DJ-1,
memeli hedef rapamisin (mTOR), Mdm2 ve Akt-1 faktörleriyle PH’nin klinik alt
tipleri arasında korelasyon belirlendi.

Sonuç: Pro-apoptotik PTEN ve anti-apoptotik
PI3K/Akt yolağının ekspresyon seviyelerinde görülen değişiklik PH’de artan
nöronal yıkımı kompanse etmek amacıyla anti-apoptotik yolaklarının
etkinleştirildiğini düşündürmektedir. Çeşitli PI3K/Akt yolağı ekspresyon
düzeyleri ile klinik parametreler arasında korelasyon saptanması PH olgularında
bu faktörlerin özürlülük ve prognoz belirteci olarak kullanılabileceğini
göstermektedir. Özellikle postural instabilite ile anti-apoptotik faktör
arasındaki ekspresyon değişikliği nöronal yıkımı akla getirmektedir.

Anahtar Kelimeler

Parkinson Hastalığı, apoptoz, PTEN, alfa-sinüklein, PI3K/Akt, PI3K/Akt

Comparison of The Expression Levels of PI3K/Akt Pathway Factors in Parkinson’s Disease and Lung Cancer

Öz

DOI: 10.26650/experimed.2018.18003

Objectives: Parkinson’s disease (PD) is a
common neurodegenerative disorder that affects >0.2% of the population aged
>40 years. Several studies have reported a low prevalence of cancer in
individuals with PD. Therefore, the PI3K/Akt signaling pathway has received
increasing research attention. Investigating variations in expression levels of
components associated with this pathway might aid in improving novel treatment
methods and biomarkers for PD.

Material and Method: We evaluated
expression levels of components of the DJ-1-PI3K/Akt signaling pathway in the
peripheral blood mononuclear cells of patients with PD, those with lung cancer
(LC), and healthy controls and attempted to identify a possible correlation
between expression levels and clinical features of PD.

Results: Levels of phosphatase and tensin
homolog (PTEN) and apoptosis-inducing factor-1 significantly decreased, whereas
those of insulin-like growth factor 1 (IGF-1) significantly increased in
patients with PD than in healthy controls. In patients with LC, levels of PTEN,
caspase-3, and α-synuclein significantly increased, whereas those of IGF-1
significantly decreased. Furthermore, a correlation was observed between the
clinical subtypes of PD and levels of α-synuclein, IGF-1, caspase-3, DJ-1,
mechanistic target of rapamycin, Mdm2, and Akt-1 factors.

Conclusion: Patients with PD showed
decreased expression levels of proapoptotic PTEN and increased levels of
components of the antiapoptotic PI3K/Akt pathway, which suggests an activation
of the antiapoptotic pathway to compensate for the increased neuronal
destruction in PD. The correlation between expression levels of components of
several PI3K/Akt signaling pathway and clinical parameters suggests that these
factors can be used as disability and prognostic markers in patients with PD.
Decreased expression levels of antiapoptotic factors in patients with PD having
postural instability, in particular, suggests a close relationship between
neuronal destruction and this symptom.

Anahtar Kelimeler

Parkinson’s Disease, apoptosis, PTEN, alpha-synuclein, PI3K/Akt

Kaynakça

• 1. de Rijk MC, Tzourio C, Breteler MM, Dartigues JF, Amaducci L, Lopez-Pousa S, et al. Prevalence of parkinsonism and Parkinson’s disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson’s disease. J Neurol Neurosurg Psychiatry 1997; 62: 10-5.
• 2. Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, Bloch DA, et al. Incidence of Parkinson’s Disease: Variation by Age, Gender, and Race/Ethnicity. Am J Epidemiol 2003; 157: 1015-22.
• 3. Hirsch E, Graybiel A, Agid Y. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 1988; 334(6180): 345-8.
• 4. Dias V, Junn E, Mouradian MM. The role of oxidative stress in parkinson’s disease. J Parkinsons Dis 2013; 3: 461-91.
• 5. Jansson B, Jankovic J. Low cancer rates among patients with Parkinson’s disease. Ann Neurol 1985; 17: 505-9.
• 6. Olsen J, Friis S, Frederiksen K. Malignant Melanoma and Other Types of Cancer Preceding Parkinson Disease. Epidemiology 2006; 17: 582-7.
• 7. D’Amelio M, Ragonese P, Morgante L, Epifanio A, Callari G, Salemi G, et al. Tumor diagnosis preceding Parkinson’s disease: A case-control study. Mov Disord 2004; 19: 807-11.
• 8. Elbaz A, Peterson B, Yang P, Van Gerpen J, Bower J, Maraganore D, et al. Nonfatal cancer preceding parkinson’s disease: a case-control study. Epidemiology 2002; 13: 157-64.
• 9. Kim R, Mak T. Tumours and tremors: how PTEN regulation underlies both. Br J Cancer 2006; 94: 620-4.
• 10. Cheng CM, Reinhardt RR, Lee WH, Joncas G, Patel SC, Bondy CA. Insulin-like growth factor 1 regulates developing brain glucose metabolism. Proc Natl Acad Sci USA 2000; 97: 10236-41.
• 11. Huang T, Verkhratsky A, Fernyhough P. Insulin enhances mitochondrial inner membrane potential and increases ATP levels through phosphoinositide 3-kinase in adult sensory neurons. Mol Cell Neurosci 2005; 28: 42-54.
• 12. Kim RH, Peters M, Jang Y, Shi W, Pintilie M, Fletcher GC, et al. DJ-1, a novel regulator of the tumor suppressor PTEN. Cancer Cell 2005; 7: 263-73.
• 13. Yang Y, Gehrke S, Haque M, Imai Y, Kosek J, Yang L et al. Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling. Proc Natl Acad Sci USA 2005; 102: 13670-5.
• 14. Fallon L, Bélanger CM, Corera AT, Kontogiannea M, Regan-Klapisz E, Moreau F, et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K–Akt signalling. Nat Cell Biol 2006; 8: 834-42.
• 15. Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, et al. Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 2005; 102: 5215-20.
• 16. Malagelada C, Jin ZH, Greene LA. RTP801 Is Induced in Parkinson’s disease and mediates neuron death by inhibiting Akt phosphorylation/activation. J Neurosci 2008; 28: 14363-71.
• 17. Timmons S, Coakley MF, Moloney AM, O’ Neill C. Akt signal transduction dysfunction in Parkinson’s disease. Neurosci Lett 2009; 467: 30-5.
• 18. Namikawa K, Honma M, Abe K, Takeda M, Mansur K, Obata T, et al. Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J Neurosci 2000; 20: 2875-86.
• 19. D’Astous M, Mendez P, Morissette M, Garcia-Segura LM, Di Paolo T. Implication of the phosphatidylinositol-3 kinase/protein kinase B signaling pathway in the neuroprotective effect of estradiol in the striatum of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine mice. Mol Pharmacol 2006; 69: 1492-8.
• 20. Ruan, H, Yang Y, Zhu X, Wang X, Chen R. Neuroprotective effects of (±)-catechin against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - induced dopaminergic neurotoxicity in mice. Neurosci Lett 2009; 450: 152-7.
• 21. Fukui M, Choi HJ, Zhu BT. Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death. Free Radic Biol Med 2010; 49: 800-13.
• 22. Qin R, Li X, Li G, Tao L, Li Y, Sun J, et al. Protection by tetrahydroxystilbene glucoside against neurotoxicity induced by MPP+: The involvement of PI3K/Akt pathway activation. Toxicol Lett 2011; 202: 1-7.
• 23. Jiang H, Guo W, Liang X, Rao Y. Both the establishment and the maintenance of neuronal polarity require active mechanisms: Critical roles of GSK-3β and its upstream regulators. Cell 2005; 120: 123-35.
• 24. Canet-Aviles RM, Wilson MA, Miller DW, Ahmad R, McLendon C, Bandyopadhyay S, et al. The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc Natl Acad Sci 2004; 101: 9103-8.
• 25. Zhang L, Shimoji M, Thomas B, Moore DJ, Yu SW, Marupudi NI, et al. Mitochondrial localization of the Parkinson’s disease related protein DJ-1: Implications for pathogenesis. Hum Mol Genet 2005; 14: 2063-73.
• 26. Blackinton J, Kumaran R, van der Brug MP, Ahmad R, Olson L, Galter D, et al. Post-transcriptional regulation of mRNA associated with DJ-1 in sporadic Parkinson disease. Neurosci Lett 2009; 452: 8-11.
• 27. Cohen AS, Lin DD, Quirk GL, Coulter DA. Dentate granule cell GABAAreceptors in epileptic hippocampus: Enhanced synaptic efficacy and altered pharmacology. Eur J Neurosci 2003; 17: 1607-16.
• 28. Ludwig A, Li H, Saarma M, Kaila K, Rivera C. Developmental up-regulation of KCC2 in the absence of GABAergic and glutamatergic transmission. Eur J Neurosci 2003; 18: 3199-206.
• 29. Ali IU, Schriml LM, Dean M. Mutational spectra of PTEN/MMAC1 gene: A tumor suppressor with lipid phosphatase activity. J Nat Cancer Inst 1999; 91: 1922-32.
• 30. Maehama T, Taylor GS, Dixon JE. PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem 2001;70: 247-79.