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Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells
Author(s) -
Bjelica Sunčica,
Diklić Miloš,
Đikić Dragoslava,
Kovačić Marijana,
Subotički Tijana,
MitrovićAjtić Olivera,
Radojković Milica,
Čokić Vladan P.,
Santibanez Juan F.
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14927
Subject(s) - bystander effect , senescence , cell growth , dna damage , biology , cell cycle , mesenchymal stem cell , microbiology and biotechnology , cancer research , reactive oxygen species , cell , immunology , dna , biochemistry
Hydroxyurea (HU) is a nonalkylating antineoplastic agent used in the treatment of hematological malignancies. HU is a DNA replication stress inducer, and as such, it may induce a premature senescence‐like cell phenotype; however, its repercussion on bystander cell proliferation has not been revealed so far. Our results indicate that HU strongly inhibited peripheral blood mesenchymal stromal cells (PBMSC) proliferation by cell cycle arrest in S phase, and that, consequently, PBMSC acquire senescence‐related phenotypical changes. HU‐treated PBMSC display increased senescence‐associated β‐galactosidase levels and p16 INK4 expression, as well as DNA damage response and genotoxic effects, evidenced by expression of γH2A.X and micronuclei. Moreover, HU‐induced PBMSC senescence is mediated by increased reactive oxygen species (ROS) levels, as demonstrated by the inhibition of senescence markers in the presence of ROS scavenger N ‐acetylcysteine and NADPH oxidase inhibitor Apocynin. To determine the HU‐induced bystander effect, we used the JAK2V617F ‐positive human erythroleukemia 92.1.7 (HEL) cells. Co‐culture with HU‐induced senescent PBMSC (HU‐S‐PBMSC) strongly inhibited bystander HEL cell proliferation, and this effect is mediated by both ROS and transforming growth factor (TGF)‐β expression. Besides induction of premature senescence, HU educates PBMSC toward an inhibitory phenotype of HEL cell proliferation. Finally, our study contributes to the understanding of the role of HU‐induced PBMSC senescence as a potential adjuvant in hematological malignancy therapies.