Oral submucous fibrosis (OSF) is a precancerous lesion of the oral cavity. Areca nut consumption can cause OSF through sustained activation of buccal mucosal fibroblasts (BMFs). This study explored the effect of curcumin on arecoline-induced BMF activation and its mechanism of action. BMFs were isolated and identified by immunofluorescence detection of fibroblast surface markers vimentin and S100A4. After transfection with FOSL1- or MAPK8-related vectors, BMFs were activated by arecoline and treated with curcumin. Scratch and transwell assays were performed to detect cell migration. ChIP and luciferase reporter assays were conducted to detect the binding of FOSL1 to the MAPK8 promoter. RT-qPCR was used to detect FOSL1 and MAPK8 mRNA expression. Western blotting was used to detect FOSL1, MAPK8, COL1A1, α-SMA, Smad2, and p-Smad2 proteins. Curcumin treatment inhibited arecoline-induced fibroblast migration, reduced the expression of myofibroblast markers COL1A1, α-SMA, and p-Smad2, and downregulated the expression of FOSL1 and MAPK8. FOSL1 or MAPK8 overexpression enhanced migration and increased COL1A1, α-SMA, and p-Smad2 expression in curcumin-treated cells. FOSL1 bound to the MAPK8 promoter and promoted MAPK8 expression. Simultaneous FOSL1 overexpression and MAPK8 knockdown, compared to FOSL1 overexpression, reduced cell migration and inhibited COL1A1, α-SMA, and p-Smad2 expression. In conclusion, curcumin targets FOSL1 to reduce MAPK8 expression, thereby suppressing arecoline-induced fibroblast activation.
Zhuo Xiqian,Li Yunfeng,Qiu Ling,Aishajiang Reyida,Lei Pengpeng,Wang Tiejun,Yu Duo
Radiotherapy plays a pivotal role in the management of
nonsmall-cell
lung cancer (NSCLC), particularly for patients who are not candidates
for surgical intervention. Despite its significance, the issue of
radioresistance remains a substantial challenge in the treatment of
the NSCLC. Therefore, it is crucial to uncover new targets to enhance
radiotherapy and investigate the mechanisms underlying radioresistance.
Cuproptosis, as an emerging form of cell death dependent on intracellular
copper (Cu) ions, remains unclear in its role in radioresistant NSCLCs.
This study investigates the development of radioresistant NSCLC models,
focusing on the role of the FOS-like antigen 1 (FOSL1) as a significant
factor in mediating radioresistance. The FOSL1 gene is downregulated
in radioresistant cells. Overexpression of FOSL1 induces mitochondrial
damage and dysfunction, causing cuproptosis in radioresistant cells.
To tackle the challenge of radioresistance in NSCLC, we propose an
innovative nanostrategy focused on cuproptosis, aiming to enhance
the efficacy of radiotherapy specifically in radioresistant NSCLC.
This intervention could significantly enhance an increase in intracellular
Cu 2+ concentration and glutathione depletion while also
increasing irradiation (IR)-induced oxidative stress and mitochondrial
damage. The resulting mitochondrial dysfunction leads to tricarboxylic
acid cycle disruption and Fe–S cluster protein destabilization.
These cumulative effects ultimately induced cuproptosis and enhanced
the response of radioresistant NSCLC cells to IR. Our findings highlight
the potential of combining cuproptosis targeting with nanotechnology
to enhance the efficacy of radiotherapy, presenting a promising strategy
to address radioresistance in clinical contexts.
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