pERK 1/2 inhibit Caspase-8 induced apoptosis in cancer cells by phosphorylating it in a cell cycle specific manner
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pERK 1/2 inhibit Caspase-8 induced apoptosis in cancer cells by phosphorylating it in a cell cycle specific manner. / Mandal, Ranadip; Raab, Monika; Matthess, Yves; Becker, Sven; Knecht, Rainald; Strebhardt, Klaus.
in: MOL ONCOL, Jahrgang 8, Nr. 2, 2014, S. 232-49.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - pERK 1/2 inhibit Caspase-8 induced apoptosis in cancer cells by phosphorylating it in a cell cycle specific manner
AU - Mandal, Ranadip
AU - Raab, Monika
AU - Matthess, Yves
AU - Becker, Sven
AU - Knecht, Rainald
AU - Strebhardt, Klaus
N1 - Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
PY - 2014
Y1 - 2014
N2 - ERK 1/2 are found to be hyperactive in many cancers. Active ERK 1/2 (pERK 1/2) are known to protect cancer cells from undergoing death receptor-mediated apoptosis, although the mechanism(s) behind this is poorly understood. Through in vitro kinase assays and mass-spectrometry we demonstrate that pERK 1/2 can phosphorylate pro-Caspase-8 at S387. Also, in EGFR-overexpressing Type I and II ovarian and breast cancer cell lines respectively, ERK 1/2 remain active only during the interphase. During this period, pERK 1/2 could inhibit Trail-induced apoptosis, most effectively during the G1/S phase. By knocking-down the endogenous pro-Caspase-8 using RNAi and replacing it with its non-phosphorylatable counterpart (S387A), a significant increase in Caspase-8 activity upon Trail stimulation was observed, even in the presence of pERK 1/2. Taken together, we propose that a combination of Trail and an inhibitor of ERK 1/2 activities could potentially enhance of Trail's effectiveness as an anti-cancer agent in ERK 1/2 hyperactive cancer cells.
AB - ERK 1/2 are found to be hyperactive in many cancers. Active ERK 1/2 (pERK 1/2) are known to protect cancer cells from undergoing death receptor-mediated apoptosis, although the mechanism(s) behind this is poorly understood. Through in vitro kinase assays and mass-spectrometry we demonstrate that pERK 1/2 can phosphorylate pro-Caspase-8 at S387. Also, in EGFR-overexpressing Type I and II ovarian and breast cancer cell lines respectively, ERK 1/2 remain active only during the interphase. During this period, pERK 1/2 could inhibit Trail-induced apoptosis, most effectively during the G1/S phase. By knocking-down the endogenous pro-Caspase-8 using RNAi and replacing it with its non-phosphorylatable counterpart (S387A), a significant increase in Caspase-8 activity upon Trail stimulation was observed, even in the presence of pERK 1/2. Taken together, we propose that a combination of Trail and an inhibitor of ERK 1/2 activities could potentially enhance of Trail's effectiveness as an anti-cancer agent in ERK 1/2 hyperactive cancer cells.
KW - Apoptosis
KW - Breast Neoplasms
KW - Caspase 8
KW - Cell Cycle
KW - Cell Line, Tumor
KW - Female
KW - Humans
KW - Mitogen-Activated Protein Kinase 1
KW - Mitogen-Activated Protein Kinase 3
KW - Neoplasm Proteins
KW - Ovarian Neoplasms
KW - Phosphorylation
U2 - 10.1016/j.molonc.2013.11.003
DO - 10.1016/j.molonc.2013.11.003
M3 - SCORING: Journal article
C2 - 24342355
VL - 8
SP - 232
EP - 249
JO - MOL ONCOL
JF - MOL ONCOL
SN - 1574-7891
IS - 2
ER -
