RSK1 vs. RSK2 inhibitory activity of the marine beta-carboline alkaloid Manzamine A: A biochemical, cervical cancer protein expression, and computational study

Mayer, Alejandro M. S. and Hall, Mary L. and Lach, Joseph and Clifford, Jonathan and Chandrasena, Kevin and Canton, Caitlin and Kontoyianni, Maria and Choo, Yeun-Mun and Karan, Dev and Hamann, Mark T. (2021) RSK1 vs. RSK2 inhibitory activity of the marine beta-carboline alkaloid Manzamine A: A biochemical, cervical cancer protein expression, and computational study. Marine Drugs, 19 (9). ISSN 1660-3397, DOI

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Manzamines are complex polycyclic marine-derived beta-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A's (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2. The effect of MZA on inhibiting cellular RSK1 and RSK2 protein expression was validated in SiHa and CaSki human cervical carcinoma cell lines. MZA's differential binding and selectivity toward the two isoforms was also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes, including growth, survival, and proliferation. Consequently, our findings have led us to hypothesize that MZA and the currently known manzamine-type alkaloids isolated from several sponge genera may have novel pharmacological properties with unique molecular targets, and MZA provides a new tool for chemical-biology studies involving RSK1.

Item Type: Article
Funders: College of Graduate Studies, Biomedical Sciences Program, Chicago College of Osteopathic Medicine, Midwestern University, Southern Illinois University Edwardsville Graduate School, NCCIH[R01AT007318], Cooper Family
Uncontrolled Keywords: MZA;Manzamine A;CTKD;C-terminal kinase domain;Ras-ERK1;2 (extracellular-signal-regulated kinase 1;2) pathway;RSK1;90 kDa ribosomal protein S6 kinase 1;RSK2;90 kDa ribosomal protein S6 kinase 2;NTKD;N-terminal kinase domain
Subjects: R Medicine
R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Science
Depositing User: Ms Zaharah Ramly
Date Deposited: 12 Sep 2022 07:29
Last Modified: 12 Sep 2022 07:29

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