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Differential effects on lung cancer cell proliferation by agonists of glucocorticoid and PPARα receptors
Huiyun Liang1, Piotr Kowalczyk, Jacob J Junco
1Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas; Medical Research Division, Regional Academic Health Center at Edinburg, University of Texas Health Science Center at San Antonio, Edinburg, Texas.
Abstract:
Glucocorticoids (GCs) are well-known anti-inflammatory compounds, but they also inhibit cell proliferation depending on cell type. Similarly, peroxisome proliferator-activated receptors (PPARα, PPARδ, and PPARγ) also possess anti-proliferation properties beyond their canonical roles as metabolic mediators. In the present study, we investigated the potential additive or synergistic inhibitory effects on cancer cell proliferation by simultaneous application of fenofibrate and budesonide, agonists for PPARα and glucocorticoid receptor, respectively. We observed differential effects on cell proliferation in A549 and SK-MES-1 lung cancer cells by budesonide and fenofibrate. Fenofibrate inhibited cell proliferation in both TP53 wild type and deficient lung cancer cells. The anti-proliferation effect of budesonide in TP53 wild type A549 cells was abolished in SK-MES-1 cells that do not have wild type TP53 protein. An additive effect against cell proliferation by budesonide and fenofibrate combination was observed only in TP53 wild type A549 cancer cells. Analysis of cell cycle distribution and cyclin profile indicated that the inhibition of cell proliferation was associated with G1 cell cycle arrest. The suppression of NF-κB activity and ERK signaling may contribute to the inhibition of cell proliferation by budesonide and or fenofibrate. The additive inhibitory effect on cell proliferation by budesonide and fenofibrate combination suggests that the same or greater therapeutic effect could be achieved with reduced dosage and side effects when the two compounds are applied simultaneously.
Insights
Glucocorticoids (GCs) and fenofibrate show anti-proliferation effects in lung cancer cells. Combining these drugs, particularly in TP53 wild-type cells, enhances this effect, suggesting reduced dosages may be possible.
Area of Science:
- Pharmacology
- Cancer Biology
- Cell Signaling
Background:
- Glucocorticoids (GCs) and peroxisome proliferator-activated receptors (PPARs) exhibit anti-proliferative properties.
- PPAR agonists, like fenofibrate, and GCs, like budesonide, have distinct effects on cell proliferation.
- The interplay between these drug classes and TP53 status in lung cancer is not fully understood.
Purpose of the Study:
- To investigate the combined effects of fenofibrate (PPARα agonist) and budesonide (glucocorticoid receptor agonist) on lung cancer cell proliferation.
- To determine if these effects are additive or synergistic, and if they are influenced by TP53 gene status.
- To explore the underlying mechanisms, including cell cycle regulation and signaling pathways.
Main Methods:
- Treatment of A549 (TP53 wild-type) and SK-MES-1 (TP53 mutated) lung cancer cells with fenofibrate and budesonide, individually and in combination.
- Cell proliferation assays to quantify drug effects.
- Cell cycle analysis and Western blotting to assess protein expression and signaling pathway activity (NF-κB, ERK).
Main Results:
- Fenofibrate inhibited proliferation in both cell lines, irrespective of TP53 status.
- Budesonide's anti-proliferative effect was observed in TP53 wild-type A549 cells but diminished in SK-MES-1 cells.
- Additive inhibition of proliferation by the combination was significant only in TP53 wild-type A549 cells, associated with G1 cell cycle arrest and suppressed NF-κB/ERK signaling.
Conclusions:
- The combination of fenofibrate and budesonide exhibits an additive anti-proliferative effect in TP53 wild-type lung cancer cells.
- This combination therapy may allow for reduced dosages, potentially minimizing side effects.
- TP53 status is a critical determinant of the response to budesonide and the combined therapy.
