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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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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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Acknowledgements

Supported by funds from Peplin Ltd and the European Commission (LSHB-CT-2004-503467). E.E. and O.B. were supported by the Norwegian Cancer Society.

Conflict of interest statement

The authors declare no conflict of interest.

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Authors and Affiliations

  1. MRC Centre for Immune Regulation, School of Immunity and Infection, Birmingham University Medical School, Birmingham, B15 2TT, UK

    Peter Hampson, Keqing Wang, Lisa Milverton & Janet M. Lord

  2. Section for Haematology, Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway

    Elisabeth Ersvaer & Oystein Bruserud

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  1. Peter Hampson
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  2. Keqing Wang
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  3. Lisa Milverton
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  4. Elisabeth Ersvaer
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  6. Janet M. Lord
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Correspondence to Peter Hampson.

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Hampson, P., Wang, K., Milverton, L. et al. 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). Apoptosis 15, 946–955 (2010). https://doi.org/10.1007/s10495-010-0507-7

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