Utjecaj stresa endoplazmatskog retikuluma na sustav plazminogenskog aktivatora

master's thesis

• Title (english): Role of DYRK1B protein in carboplatin resistance of ovarian cancer cells
• Author: Doris Janjić
• Mentor: Maja Matulić (mentor)
• Committee member: Maja Matulić (predsjednik povjerenstva)
• Committee member: Nada Oršolić (član povjerenstva)
• Committee member: Petra Korać (član povjerenstva)
• Committee member: Inga Urlić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2024-09-18, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Sustav plazminogenskog aktivatora izvanstanični je proteolitički enzimatski sustav koji se sastoji od urokinaznog plazminogenskog aktivatora ili urokinaze (uPA), urokinaznog receptora uPAR i urokinaznog inhibitora PAI-1. Urokinaza aktivira plazminogen, pretvarajući ga u plazmin koji igra ključnu ulogu u remodeliranju izvanstaničnog matriksa, otapanju krvnih ugrušaka, migraciji i invaziji stanica, te sudjeluje u brojnim važnim fiziološkim procesima. Cilj ovog rada bio je utvrditi utječe li stres endoplazmatskog retikuluma (ER-a) na urokinaznu aktivnost stanica. Tijekom stresa ER-a, nastalog nakupljanjem nepravilno smotanih proteina, dolazi do aktivacije tri tipa transmembranskih senzora koji iniciraju i reguliraju odgovor na nesmotane proteine (UPR). Ovaj odgovor uključuje inhibiciju translacije proteina, povećanje ekspresije proteina šaperona te može dovesti do autofagije ili apoptoze. U istraživanju su korištene tumorske linije humanog glioblastoma A1235 i tumora dojke MDA-MB-231, pri čemu je stres ER-a bio induciran primjenom agensa za koje se zna da izazivaju takav stanični odgovor, ispitani su i u kombinaciji sa inhibitorima šaperona i senzornih molekula. U stanicama glioblastoma uočeno je povećanje aktivnosti uPA, dok je u stanicama tumora dojke zabilježen pad te aktivnosti. Analizirana je ekspresija uPA, PAI-1 i BiP proteina u staničnim lizatima kontrolnih i tretiranih stanica. Rezultati su pokazali da je induktor stresa ER-a značajno utjecao na urokinazni sustav u obje stanične linije, uz smanjenje migracije, invazije i proliferacije stanica. Također, inhibitori koji su smanjili učinke stresa ER-a utjecali su na aktivnost urokinaze, dok je inhibitor šaperona smanjio ekspresiju BiP-a. Zaključeno je da stres ER-a može sudjelovati u regulaciji sustava plazminogenskog aktivatora, na stanično specifičan način.

Abstract (english)

The plasminogen activator system is an extracellular proteolytic enzyme system composed of urokinase plasminogen aktivator or urokinase (uPA), the urokinase receptor uPAR, and the urokinase inhibitor PAI-1. Urokinase activates plasminogen, converting it into plasmin, which plays a crucial role in extracellular matrix remodeling, blod clot degradation, cell migration and invasion, and numerous other physiological processes. The aim of this study was to determine whether endoplasmic reticulum (ER) stress influences urokinase activity. During ER stress, triggered by the accumulation of misfolded proteins, three types of transmembrane sensors are activated, initiating and regulating the unfolded protein response (UPR). This response includes inhibition of protein translation and increased expression of chaperone proteins, which can lead to autophagy or apoptosis. In this study human glioblastoma cell line A1235 and breast cancer cell line MDA-MB-231 were used, ER stress was induced by agents known to cause such cellular responses and agents were further examined in combination with chaperone inhibitor and inhibitor of the sensor molecule. In glioblastoma cells, an increase in uPA activity was observed, while a decrease was observed in breast cancer cells. The expression of uPA, PAI-1, and BiP proteins was analyzed in cell lysates from both control and treated cells. The results demonstrated that ER stress inductor significantly affected the urokinase system in both cell lines, leading to reduced cell migration, invasion, and proliferation. Additionally, inhibitors reduced the effects of ER stress on urokinase activity, while the chaperone inhibitor decreased BiP expression. The results suggest that ER stress may regulate the plasminogen activator system in a cell-specific manner.

• Keywords: urokinazni plazminogenski aktivator; PAI-1; uPAR; stres ER-a; glioblastom; tumor dojke; aktivnost; ekspresija
• Keywords (english): urokinase plasminogen activator; PAI-1; uPAR; ER stress; glioblastoma; breast cancer; activity; expression
• Language: croatian
• URN:NBN: urn:nbn:hr:217:913454
• Project: Number: IP-2020-02-2431; Title: Obnova timusa za preciznu medicinu u liječenju tumora i leukemija; Title: Thymus renewal for precision medicine in cancer and leukaemia treatment; Acronym: THYMINNOVA; Leader: Mariastefania Antica; Jurisdiction: Croatia; Funder: Hrvatska zaklada za znanost; Funding stream: Research Projects
• Study programme: Title: Experimental Biology-University graduate programme; Study programme type: university; Study level: graduate; Academic / professional title: sveučilišni/a magistar/magistra eksperimentalne biologije (sveučilišni/a magistar/magistra eksperimentalne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-09-30 10:17:50