Treatment of chronic myeloid leukemia cells with imatinib (STI571) impairs p53 accumulation in response to DNA damage.
Chronic myelogenous leukaemia (CML) is induced by the Bcr-Abl fusion protein. Inhibition of Bcr-Abl by STI571 is widely used to treat CML patients. Unlike in most cancer types, the frequency of p53 mutations in CML is low. Here, we investigated the effect of STI571 treatment of CML cells on p53 regulation. Exposure of CML cells, including established cell lines and freshly isolated cells from patients, to STI571 reduced p53 protein levels, and severely impaired its accumulation in response to DNA damage. This may be explained by the status of p53 serine 20 phosphorylation. In non-stressed CML cells, serine 20 of p53 is constitutively phosphorylated by Chk1, and is inhibited by STI571. In response to DNA damage, however, this phosphorylation is mediated by Chk1 and Chk2, and is only partially inhibited by STI571. CML cells expressing wild-type p53 are more resistant to treatment with STI571, but moderately more sensitive to DNA damage, than CML cells lacking p53. An enhanced induction of apoptosis by STI571 and DNA damage is observed in CML cells bearing wild-type p53, but not in cells lacking functional p53. This implies that the status of p53 may affect the response of CML cells to this combined treatment.
Lautenberg Center for General and Tumor Immunology, The Hebrew Universitym, Hadassah Medical School, Jerusalem, Israel.
Zehavit
Z
Goldberg
Yaara
Y
Levav
Svetlana
S
Krichevsky
Eitan
E
Fibach
Ygal
Y
Haupt
D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D002460:Cell Line; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D012694:Serine; D000068877:Imatinib Mesylate; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases