Marine alkaloid monanchoxymycalin C: a new specific activator of JNK1/2 kinase with anticancer properties
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Marine alkaloid monanchoxymycalin C: a new specific activator of JNK1/2 kinase with anticancer properties. / Dyshlovoy, Sergey A; Kaune, Moritz; Kriegs, Malte; Hauschild, Jessica; Busenbender, Tobias; Shubina, Larisa K; Makarieva, Tatyana N; Hoffer, Konstantin; Bokemeyer, Carsten; Graefen, Markus; Stonik, Valentin A; von Amsberg, Gunhild.
In: SCI REP-UK, Vol. 10, No. 1, 06.08.2020, p. 13178.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Marine alkaloid monanchoxymycalin C: a new specific activator of JNK1/2 kinase with anticancer properties
AU - Dyshlovoy, Sergey A
AU - Kaune, Moritz
AU - Kriegs, Malte
AU - Hauschild, Jessica
AU - Busenbender, Tobias
AU - Shubina, Larisa K
AU - Makarieva, Tatyana N
AU - Hoffer, Konstantin
AU - Bokemeyer, Carsten
AU - Graefen, Markus
AU - Stonik, Valentin A
AU - von Amsberg, Gunhild
PY - 2020/8/6
Y1 - 2020/8/6
N2 - Monanchoxymycalin C (MomC) is a new marine pentacyclic guanidine alkaloid, recently isolated from marine sponge Monanchora pulchra by us. Here, anticancer activity and mechanism of action was investigated for the first time using a human prostate cancer (PCa) model. MomC was active in all PCa cell lines at low micromolar concentrations and induced an unusual caspase-independent, non-apoptotic cell death. Kinase activity screening identified activation of mitogen-activated protein kinase (MAPK) c-Jun N-terminal protein kinase (JNK1/2) to be one of the primary molecular mechanism of MomC anticancer activity. Functional assays demonstrated a specific and selective JNK1/2 activation prior to the induction of other cell death related processes. Inhibition of JNK1/2 by pretreatment with the JNK-inhibitor SP600125 antagonized cytotoxic activity of the marine compound. MomC caused an upregulation of cytotoxic ROS. However, in contrast to other ROS-inducing agents, co-treatment with PARP-inhibitor olaparib revealed antagonistic effects indicating an active PARP to be necessary for MomC activity. Interestingly, although no direct regulation of p38 and ERK1/2 were detected, active p38 kinase was required for MomC efficacy, while the inhibition of ERK1/2 increased its cytotoxicity. In conclusion, MomC shows promising activity against PCa, which is exerted via JNK1/2 activation and non-apoptotic cell death.
AB - Monanchoxymycalin C (MomC) is a new marine pentacyclic guanidine alkaloid, recently isolated from marine sponge Monanchora pulchra by us. Here, anticancer activity and mechanism of action was investigated for the first time using a human prostate cancer (PCa) model. MomC was active in all PCa cell lines at low micromolar concentrations and induced an unusual caspase-independent, non-apoptotic cell death. Kinase activity screening identified activation of mitogen-activated protein kinase (MAPK) c-Jun N-terminal protein kinase (JNK1/2) to be one of the primary molecular mechanism of MomC anticancer activity. Functional assays demonstrated a specific and selective JNK1/2 activation prior to the induction of other cell death related processes. Inhibition of JNK1/2 by pretreatment with the JNK-inhibitor SP600125 antagonized cytotoxic activity of the marine compound. MomC caused an upregulation of cytotoxic ROS. However, in contrast to other ROS-inducing agents, co-treatment with PARP-inhibitor olaparib revealed antagonistic effects indicating an active PARP to be necessary for MomC activity. Interestingly, although no direct regulation of p38 and ERK1/2 were detected, active p38 kinase was required for MomC efficacy, while the inhibition of ERK1/2 increased its cytotoxicity. In conclusion, MomC shows promising activity against PCa, which is exerted via JNK1/2 activation and non-apoptotic cell death.
U2 - 10.1038/s41598-020-69751-z
DO - 10.1038/s41598-020-69751-z
M3 - SCORING: Journal article
C2 - 32764580
VL - 10
SP - 13178
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -