Uloga signalnoga puta AMPK/mTOR u diferencijaciji leukemijskih stanica [The role of AMPK/mTOR signaling pathway in differentiation of leukemia cells]

Lalić, Hrvoje (2015) Uloga signalnoga puta AMPK/mTOR u diferencijaciji leukemijskih stanica [The role of AMPK/mTOR signaling pathway in differentiation of leukemia cells]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Pharmacological modulators of adenosine monophosphate (AMP)-activated kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway have been shown to exert antiproliferative effects but their role in the differentiation of acute myeloid leukemia (AML) is less explored. The aim of this study was to determine the role of AMPK/mTOR pathway in differentiation of AML cell lines. The results showed that rapamycin, an mTOR inhibitor, enhanced the inhibitory effects of two granulocytic inducers, all-trans retinoic acid (ATRA) and dimethyl-sulphoxide (DMSO), on the number of viable AML cells. Rapamycin enhanced the expression of differentiation markers in ATRA-treated NB4 cells, and increased apoptosis in NB4 cells differentiated with DMSO. Two AMPK modulators, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and metformin, were shown to inhibit the activity of mTOR and reduce the proliferation of AML cells. AICAR enhanced the expression of differentiation markers in ATRA-treated NB4 cells and induced the expression of markers associated with mature monocytes and macrophages in U937 cells. AICAR-mediated effects were independent of AMPK and associated with an increase in the activity of mitogen-activated protein kinase (MAPK). These results reveal beneficial effects of an mTOR inhibitor and an AMPK agonist in differentiation of AML cell lines.

Abstract in Croatian

Prethodna istraživanja pokazala su da farmakološki modulatori signalnog puta adenozin-monofosfat (AMP)-aktivirane kinaze (AMPK)/mTOR (prema engl. mammalian/mechanistic target of rapamycin) koče proliferaciju stanica akutne mijeloične leukemije (AML), ali njihova uloga u diferencijaciji je manje istražena. Cilj ovog istraživanja bio je odrediti ulogu signalnog puta AMPK/mTOR u diferencijaciji staničnih linija AML-a. Rezultati su pokazali da rapamicin, inhibitor mTOR-a, pospješuje učinke dvaju promicatelja granulocitne diferencijacije, sve-trans retinske kiseline (ATRA, prema engl. all-trans retinoic acid) i dimetil-sulfoksida (DMSO), na smanjenje broja živih stanica AML-a. Rapamicin je pospješio izražaj diferencijacijskih biljega u stanicama NB4 koje su tretirane ATRA-om te povećao apoptozu u stanicama NB4 koje su diferencirane DMSO-om. 5-aminoimidazol-4-karboksamid ribonukleozid (AICAR) i metformin, oba modulatori AMPK-a, zakočili su aktivnost mTOR-a i smanjili proliferaciju stanica AML-a. AICAR je pospješio izražaj diferencijacijskih biljega u stanicama NB4 koje su tretirane ATRA-om te potaknuo izražaj biljega zrelih monocita i makrofaga u stanicama U937. Učinci AICAR-a nisu ovisni o AMPK-u, a povezani su s povećanjem aktivnosti mitogenom aktivirane proteinske kinaze (MAPK). Ovi rezultati pokazuju povoljne učinke inhibitora mTOR-a i agonista AMPK-a na diferencijaciju staničnih linija AML-a.

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