Naslov
DNA damage pathway contributes to monocytic differentiation

Autori
Tomić, Barbara ; Dembitz, Vilma ; Višnjić, Dora

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Skup
2020 Annual Meeting of the Croatian Immunological Society

Mjesto i datum
Zagreb, Hrvatska, 01.10.2020. - 02.10.2020

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Podatak o recenziji nije dostupan

Ključne riječi
DNA damage ; differentiation

Sažetak
Our previous studies showed that 5-aminoimidazole- 4-carboxamide ribonucleoside (AICAr), a known metabolic modulator, induces differentiation of monocytic cell lines by pyrimidine depletion and subsequent activation of the ataxia telangiectasia and RAD3-related (ATR)/checkpoint kinase 1 (Chk1)-mediated signaling pathway. Apart from nucleotide pool depletion, DNA damage response network can also be activated due to replication stress following integration of nucleotide analogues. Cytarabine or cytosine arabinoside (ara-C), an antimetabolite analogue of cytidine, interferes with DNA replication by multiple mechanisms, primarily by incorporation into DNA molecule. Cytarabine is widely used as a chemotherapeutic drug in acute myeloid leukemia (AML) treatment for more than several decades. It is well known that, apart from its cytotoxic effects, cytarabine stimulates differentiation of leukemic cells, but the exact mechanism remains to be elucidated. The aim of the present study is to test for the possible role of ATR/Chk1 in cytarabine- mediated effects and to further define DNA-damage pathway responsible for monocytic differentiation, in particular the involvement of Cyclin-dependent kinase 1 (Cdk1). Our results show that cytarabine dose-dependently mimics the effects of pyrimidine synthesis inhibitors on the number of viable cells and the expression of differentiation markers in monocytic cell lines. Moreover, cytarabine dose-dependently increased the level of Ser-345-phosphorylated Chk1, and all agents tested increased the level of Tyr-15- phosphorylated Cdk1. Pharmacological inhibition of ATR/Chk1 pathway by Torin2 and VE-821, as well as siRNA-mediated Chk1 knockdown, diminished the effects on differentiation. Therefore, our preliminary data suggest that cytarabine- mediated monocytic differentiation occurs via ATR/Chk1 signaling pathway.

Izvorni jezik
Engleski

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