Marine alkaloid monanchoxymycalin C: a new specific activator of JNK1/2 kinase with anticancer properties
Dyshlovoy, S.A.; Kaune, M.; Kriegs, M.; Hauschild, J.; Busenbender, T.; Shubina, L.K.; Makarieva, T.N.; Hoffer, K.; Bokemeyer, C.; Graefen, M.; Stonik, V.A.; von Amsberg, G. (2020). Marine alkaloid monanchoxymycalin C: a new specific activator of JNK1/2 kinase with anticancer properties. NPG Scientific Reports 10(1): 14 pp. https://dx.doi.org/10.1038/s41598-020-69751-z
In: Scientific Reports (Nature Publishing Group). Nature Publishing Group: London. ISSN 2045-2322; e-ISSN 2045-2322, more
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| Keyword |
Monanchora pulchra (Lambe, 1895) [WoRMS]
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| Authors | | Top |
- Dyshlovoy, S.A.
- Kaune, M.
- Kriegs, M.
- Hauschild, J.
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- Busenbender, T.
- Shubina, L.K.
- Makarieva, T.N.
- Hoffer, K.
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- Bokemeyer, C.
- Graefen, M.
- Stonik, V.A.
- von Amsberg, G.
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| Abstract |
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. |
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