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

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.