Abstract
Background: Targeting inflammatory microenvironment is a promising anti-tumor strategy. Paeonol is a phenolic compound with effective anti-inflammatory and anti-tumor properties. However, the effects of paeonol on non-small cell carcinoma (NSCLC) have not been fully investigated. Here, we evaluated the effects of paeonol on proliferation and metastasis of NSCLC and elucidated the underlying mechanisms. Methods: The effects of paeonol on inflammatory cytokines were determined by cell proliferation and ELISA assays. Assays of wound healing, single cell migration and perforation invasion were used to evaluate migration and invasion of NSCLC cells. Expression of marker proteins in epithelial-mesenchymal transition (EMT) and matrix metalloproteinase (MMP) family enzymes were detected by Western blot assays. Nude mouse A549 cells transplantation tumor model was used to study the anti-lung cancer effects of paeonol in vivo. TUNEL stanining were used to detect the apoptosis of tumor cells in A549 lung cancer mice, and Ki67 analysis was used to detect the proliferation of tumor cells in A549 lung cancer mice. Immunohistochemistry was used to detect the effects of paeonol on signaling molecules in tumor tissues. Results: Paeonol inhibited A549 cancer cell migration and invasion in vitro. Paeonol inhibited secreaion of inflammatory cytokines in A549 cells, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and transforming growth factor (TGF)-β. Paeonol altered the expression of marker proteins involved in EMT and MMP family enzymes. In addition, paeonol inhibited the transcriptional activity of nuclear factor-κB (NF-κB) and phosphorylation of signal transducers and activators of transcription 3 (STAT3). Paeonol inhibited the growth of A549 cells transplanted tumors in nude mice. Conclusion: Paeonol potently inhibited NSCLC cell growth, migration and invasion associated with disruption of STAT3 and NF-κB pathways, suggesting that it could be a promising anti-metastatic candidate for tumor chemotherapy.
Highlights
Lung carcinogenesis has been recognized as one of the hallmarks of human cancer, and recently shows a strong connection with inflammation (Altorki et al, 2019; Mohrherr et al, 2020)
We report that paeonol potently inhibited A549 cancer cell migration and invasion associated with disruption of signal transducers and activators of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) pathways, suggesting that it may be a promising antimetastatic candidate for lung tumor chemotherapy
The results showed that paeonol at 80 μg/ml significantly altered the morphology of the three cell lines, and at 40 μg/ml remarkably affect the morphology of A549 cells
Summary
Lung carcinogenesis has been recognized as one of the hallmarks of human cancer, and recently shows a strong connection with inflammation (Altorki et al, 2019; Mohrherr et al, 2020). The infiltrated inflammatory cells produce different cytokines and chemokines to promote tumor cell migration and invasion and contribute to inflammation-mediated metastasis (Wu and Zhou, 2010; Yi et al, 2017). Numbers of cancer-related cytokines frequently precede and contribute to NSCLC development (Zhang J. et al, 2019). These cancer-related cytokines can activate several signal pathways, such as NF-κB and JAK/STAT, which control cancer cell proliferation, survival, and chemosensitivity (Ivanenkov et al, 2011; Garbers et al, 2015). Many pharmacological interventions have been developed to target inflammatory mediators and immune-related signal pathways. Agents attacking multiple inflammatory signaling pathways may effectively prevent the proliferation and metastasis of tumor cells. We evaluated the effects of paeonol on proliferation and metastasis of NSCLC and elucidated the underlying mechanisms
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