Τίτλος:
The roles of p27Kip1 and DNA damage signalling in the chemotherapy-induced delayed cell cycle checkpoint
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
DNA lesions trigger the DNA damage response (DDR) machinery, which protects genomic integrity and sustains cellular survival. Increasing data underline the significance of the integrity of the DDR pathway in chemotherapy response. According to a recent work, persistent exposure of A549 lung carcinoma cells to doxorubicin induces an initial DDR-dependent checkpoint response, followed by a later DDR-independent, but p27Kip1-dependent one. Prompted by the above report and to better understand the involvement of the DDR signaling after chemotherapeutic stress, we examined the potential role of the canonical DDR pathway in A549 cells treated with doxorubicin. Exposure of A549 cells, prior to doxorubicin treatment, to ATM, ATR and DNA-PKcs inhibitors either alone or in various combinations, revealed that the earlier documented two-step response was DDR-dependent in both steps. Notably, inhibition of both ATM and ATR or selective inhibition of ATM or DNA-PKcs resulted in cell-cycle re-entry despite the increased levels of p27Kip1 at all time points analyzed. We further investigated the regulation of p27Kip1 protein levels in the particular setting. Our results showed that the protein status of p27Kip1 is mainly determined by p38-MAPK, whereas the role of SKP2 is less significant in the doxoroubicin-treated A549 cells. Cumulatively, we provide evidence that the DNA damage signaling is responsible for the prolonged cell cycle arrest observed after persistent chemotherapy-induced genotoxic stress. In conclusion, precise identification of the molecular mechanisms that are activated during the chemotherapeutic cycles could potentially increase the sensitization to the therapy applied. © 2010 The Authors. Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Συγγραφείς:
Liontos, M.
Velimezi, G.
Pateras, I.S.
Angelopoulou, R.
Papavassiliou, A.G.
Bartek, J.
Gorgoulis, V.G.
Περιοδικό:
Journal of Cellular and Molecular Medicine
Λέξεις-κλειδιά:
2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; antineoplastic agent; ATM protein; ATM protein, human; caffeine; CDKN1B protein, human; chromone derivative; cyclin dependent kinase inhibitor 1B; DNA dependent protein kinase; doxorubicin; mitogen activated protein kinase p38; morpholine derivative; pyrone derivative; S phase kinase associated protein, A-549 cell line; antagonists and inhibitors; DNA damage; drug effects; G2 phase cell cycle checkpoint; human; metabolism; physiology, A549 Cells; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Caffeine; Chromones; Cyclin-Dependent Kinase Inhibitor p27; DNA Damage; DNA-Activated Protein Kinase; Doxorubicin; G2 Phase Cell Cycle Checkpoints; Humans; Morpholines; p38 Mitogen-Activated Protein Kinases; Pyrones; S-Phase Kinase-Associated Proteins
DOI:
10.1111/j.1582-4934.2010.01145.x
