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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@article{a6f57985aede495abb284d0781a3840d,
title = "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).",
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 (PKCdelta). Here we have investigated signalling events downstream of PKCdelta 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.",
keywords = "Apoptosis, ERK1/2, PKC, Acute myeloid leukaemia",
author = "Peter Hampson and Ke-Qing Wang and L Milverton and E Ersvaer and O Bruserud and Janet Lord",
year = "2010",
month = may,
day = "14",
doi = "10.1007/s10495-010-0507-7",
language = "English",
volume = "15",
pages = "946--955",
journal = "Apoptosis",
issn = "1360-8185",
publisher = "Springer",
number = "8",

}

RIS

TY - JOUR

T1 - 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).

AU - Hampson, Peter

AU - Wang, Ke-Qing

AU - Milverton, L

AU - Ersvaer, E

AU - Bruserud, O

AU - Lord, Janet

PY - 2010/5/14

Y1 - 2010/5/14

N2 - 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 (PKCdelta). Here we have investigated signalling events downstream of PKCdelta 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.

AB - 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 (PKCdelta). Here we have investigated signalling events downstream of PKCdelta 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.

KW - Apoptosis

KW - ERK1/2

KW - PKC

KW - Acute myeloid leukaemia

U2 - 10.1007/s10495-010-0507-7

DO - 10.1007/s10495-010-0507-7

M3 - Article

C2 - 20467815

VL - 15

SP - 946

EP - 955

JO - Apoptosis

JF - Apoptosis

SN - 1360-8185

IS - 8

ER -