Targeting of magnolin on ERKs inhibits Ras/ERKs/RSK2-signaling-mediated neoplastic cell transformation

Abstract

Mitogen-activated protein kinases play a key role in cell proliferation, cell cycle progression and cell transformation, and activated Ras/extracellular signal-regulated kinases (ERKs)/ribosomal S6 kinase 2 (RSK2) signaling pathways have been widely identified in many solid tumors. In this study, we found that magnolin, a compound found in the Magnolia species, directly targeted and inhibited ERK1 and ERK2 kinase activities with IC50 values of 87 and 16.5 nM by competing with adenosine triphosphate in an active pocket. Further, we demonstrated that magnolin inhibited epidermal growth factor (EGF)-induced p90RSKs phosphorylation at Thr359/Ser363, but not ERKs phosphorylation at Thr202/Tyr204, and this resulted in inhibition of cell proliferation by suppression of the G1/S cell cycle transition. Additionally, p38 kinases, Jun N-terminal kinases and Akts were not involved in the magnolin-mediated inhibitory signaling. Magnolin targeting of ERK1 and 2 activities suppressed the phosphorylation of RSK2 and downstream target proteins including ATF1 and c-Jun and AP-1, a dimer of Jun/Fos, and the transactivation activities of ATF1 and AP-1. Notably, ERKs inhibition by magnolin suppressed EGF-induced anchorage-independent cell transformation and colony growth of Ras(G12V)-harboring A549 human lung cancer cells and NIH3T3 cells stably expressing Ras(G12V) in soft agar. Taken together, these results demonstrated that magnolin might be a naturally occurring chemoprevention and therapeutic agent capable of inhibiting cell proliferation and transformation by targeting ERK1 and ERK2.

Magnolin targeting of ERK1/2 inhibits cell proliferation and colony growth by induction of cellular senescence in ovarian cancer cells

“…Moreover, we confirmed that magnolin suppressed ATF1 phosphorylation only in TOV‐112D cells, not in SKOV3 cells, under normal cell culture conditions (Figure E). Taken together with the results in our previous study, these results demonstrate that molecular targeting of ERK1 and ERK2 with magnolin can suppress ovarian cancer cell lines harboring a general MAPK signaling cascade such as TOV‐112D. These results also suggest that cells containing a bypass signaling pathway of ERK1/2 may induce chemoresistance against therapeutic compounds that target RSK upstream signaling molecules in Ras/Raf/MEKs/ERKs signaling axis.…”

“…The Ras/Raf/MEKs/ERKs/RSK2 signaling pathway has an important role in cell proliferation and cancer development by stimulation of growth factors . Our previous results demonstrated that inhibition of ERK1 and ERK2 by magnolin suppresses G1/S cell‐cycle transition in premalignant JB6 Cl41 cells . Therefore, based on the results presented in Figure and Table , we hypothesized that magnolin might differentially inhibit cell‐cycle arrest in TOV‐112D and SKOV3 ovarian cancer cells.…”

Epimagnolin targeting on an active pocket of mammalian target of rapamycin suppressed cell transformation and colony growth of lung cancer cells

“…Epimagnolin (Figure A), a natural lignan compound abundantly found in Magnolia flos, has a very similar chemical structure to those of magnolin and aschantin . Our previous studies demonstrated that magnolin and aschantin suppressed tumor promoter‐induced carcinogenesis and cancer cell proliferation . Although epimagnolin is structurally similar to magnolin, the efficacy of epimagnolin on carcinogenesis and the molecular targets of epimagnolin have not been clearly elucidated.…”

“…Epimagnolin has a chemical structure similar to those of magnolin and aschantin . Recently, our research group found that magnolin targets ERK1 and ERK2 with 87 and 16.5 nM IC 50 values, respectively . Moreover, although aschantin also has a very similar chemical structure to that of magnolin, aschantin targets mTOR kinase with an IC 50 of approximately 400 nM without affecting ERK1 and ERK2 activity .…”

Inhibitory Effects of Dimethyllirioresinol, Epimagnolin A, Eudesmin, Fargesin, and Magnolin on Cytochrome P450 Enzyme Activities in Human Liver Microsomes

“…Fargesin exhibits additional biological activities, including β1-adrenergic receptor antagonistic and cardioprotective effects [13], stimulation of basal glucose uptake and glucose transporter-4 translocation in muscle cells [14], treatment of dyslipidemia and hyperglycemia in high-fat diet-induced obese mice via activation of Akt and 5′-adenosine monophosphate-activated protein kinase in white adipose tissue [15], and antihypertensive effects in 2K1C hypertensive rats [16]. Magnolin also inhibits cancer cell migration, invasion, and growth [17,18,19] and ameliorates contrast-induced nephropathy via antioxidation and antiapoptosis in rats [20]. …”