Inhibition of p38 MAPK activity leads to cell type-specific effects on the molecular circadian clock and time-dependent reduction of glioma cell invasiveness

Abstract

BackgroundThe circadian clock is the basis for biological time keeping in eukaryotic organisms. The clock mechanism relies on biochemical signaling pathways to detect environmental stimuli and to regulate the expression of clock-controlled genes throughout the body. MAPK signaling pathways function in both circadian input and output pathways in mammals depending on the tissue; however, little is known about the role of p38 MAPK, an established tumor suppressor, in the mammalian circadian system. Increased expression and activity of p38 MAPK is correlated with poor prognosis in cancer, including glioblastoma multiforme; however, the toxicity of p38 MAPK inhibitors limits their clinical use. Here, we test if timed application of the specific p38 MAPK inhibitor VX-745 reduces glioma cell invasive properties in vitro.MethodsThe levels and rhythmic accumulation of active phosphorylated p38 MAPK in different cell lines were determined by western blots. Rhythmic luciferase activity from clock gene luciferase reporter cells lines was used to test the effect of p38 MAPK inhibition on clock properties as determined using the damped sine fit and Levenberg–Marquardt algorithm. Nonlinear regression and Akaike’s information criteria were used to establish rhythmicity. Boyden chamber assays were used to measure glioma cell invasiveness following time-of-day-specific treatment with VX-745. Significant differences were established using t-tests.ResultsWe demonstrate the activity of p38 MAPK cycles under control of the clock in mouse fibroblast and SCN cell lines. The levels of phosphorylated p38 MAPK were significantly reduced in clock-deficient cells, indicating that the circadian clock plays an important role in activation of this pathway. Inhibition of p38 MAPK activity with VX-745 led to cell-type-specific period changes in the molecular clock. In addition, phosphorylated p38 MAPK levels were rhythmic in HA glial cells, and high and arrhythmic in invasive IM3 glioma cells. We show that inhibition of p38 MAPK activity in IM3 cells at the time of day when the levels are normally low in HA cells under control of the circadian clock, significantly reduced IM3 invasiveness.ConclusionsGlioma treatment with p38 MAPK inhibitors may be more effective and less toxic if administered at the appropriate time of the day.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3896-y) contains supplementary material, which is available to authorized users.

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“…The p38–MAPK signaling pathway has been implicated in the inflammatory response, cell cycle regulation, cell death, differentiation, and tumor progression. 36 Goldsmith et al 37 reported that inhibition of the p38–MAPK pathway led to decreased glioma cell invasion. Another study found that miR-3188 promoted cell proliferation and migration via the p38–MAPK pathway in breast cancer.…”

Insights About Circadian Clock and Molecular Pathogenesis in Gliomas

“…Unlike normal HA glial cells, phosphorylated p38 MAPK levels were high and arrhythmic in invasive IM3 glioma cells. Despite this arrhythmicity in p38 MAPK phosphorylation, timed application of p38 MAPK activity inhibitor VX-745 to IM3 cells at timepoints corresponding to low activity ofP38 MAPK in HA glial cells reduced the invasive properties of IM3 cells (90).…”

The PKR/P38/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer’s Disease

“…The authors proposed that MK2 could have a role in AD brain pathology. Because many p38α inhibitors were not successful in clinical development due to their toxicological profiles inducing apoptosis [ 62 , 63 , 64 ], recent experimental attempts were initiated to find new MK2 inhibitors that could serve as anti-inflammatory agents [ 65 ]. For example, an in vitro study revealed that MK2 inhibitors could be superior to p38 inhibitors because these latter inhibitors induce increased phosphorylated C-Jun kinase (pJNK) and caspase 3 activations (leading to possible increased cellular apoptosis) as compared to MK2 inhibitors [ 66 ].…”