Kinetics of ERK1/2 activation determine sensitivity of acute myeloid leukaemia cells to the induction of apoptosis by the novel small molecule ingenol 3-angelate (PEP005) |
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Authors: | Peter Hampson Keqing Wang Lisa Milverton Elisabeth Ersvaer Oystein Bruserud Janet M Lord |
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Institution: | (1) MRC Centre for Immune Regulation, School of Immunity and Infection, Birmingham University Medical School, Birmingham, B15 2TT, UK;(2) Section for Haematology, Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway |
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Abstract: | The novel small molecule ingenol 3-angelate (PEP005) has been shown previously to induce apoptosis in leukaemic cell lines
and primary AML cells, an effect that requires the expression of protein kinase C-delta (PKCδ). Here we have investigated
signalling events downstream of PKCδ that determine sensitivity of AML cells to PEP005. We show that activation of ERK1/2
MAP kinase occurred in both sensitive and resistant cells and that induction of apoptosis required sustained signalling through
the ERK1/2 pathway. Inhibition of ERK1/2 signalling using the MEK inhibitor PD98059 inhibited PEP005-induced apoptosis and
activation of ERK1/2 was shown to occur downstream of PKC activation. The data show that PEP005-induced apoptosis is both
PKC and ERK1/2 dependent and indicate that chronic activation of ERK1/2 in leukaemic cells delivers a pro-apoptotic rather
than a proliferative or survival signal. |
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