The role of stress signals in regulating gastric cancer initiation and progression is not quite clear. It is known that stress signals modulate multiple processes such as immune function, cell migration and angiogenesis. However, few studies have investigated the mechanisms of how stress signals contribute to gastric cancer angiogenesis. Here, we used β2-adrenergic receptor (β2-AR) agonist isoprenaline to imitate a stress signal and demonstrated the molecular mechanism underlying stress’s influence on tumor angiogenesis. We found that isoprenaline stimulated vascular endothelial growth factor (VEGF) secretion in gastric cancer cells and plexin-A1 expression was induced by human recombinant VEGF165 in both gastric cancer cells and vascular endothelial cells. Furthermore, interfere with plexin-A1 expression in gastric cancer cells influence HUVEC tube formation, migration and tumor growth in vivo. These findings suggest that isoprenaline stimulate VGEF secretion and subsequently up-regulate the expression of plexin-A1 and VEGFR2 in gastric cancer cells, which form a positive impetus to promote tumor angiogenesis. This study reveals a novel molecular mechanism that a stress signal like isoprenaline may enhance angiogenesis via activating plexin-A1/VEGFR2 signaling pathway in gastric cancer, which may be a potential target in development of an anti-angiogenic therapy for gastric cancer.

Chronic stress is a common emotional disorder in cancer patients. Chronic stress promotes progression of gastric cancer (GC) and leads to poor outcomes. However, the underlying mechanisms remain not clear. Herein, we explored the possible mechanisms of chronic stress in GC progression. The Cancer Genome Atlas (TCGA) datasets were analyzed for differentially expressed genes. Clinical data of GC were evaluated for their association with PlexinA1 using TCGA and Kaplan-Meier-plotter databases. Chronic stress of GC patients was evaluated using the Self-Rating Anxiety Scale and Self-Rating Depression Scale. Chronic unpredictable mild stress (CUMS) was used to induce chronic stress in mice. Gastric xenograft tumor was constructed using the sewing method. Chronic stress-like behaviors were assessed using light/dark box and tail suspension tests. Protein expression was detected using immunohistochemistry and Western blot analysis. Analyses of TCGA and the Kaplan-Meier-plotter databases showed that patients with high levels of PlexinA1 in GC had worse overall survival than those with low levels of PlexinA1. A total of 36 GC patients were enrolled in the study, and about 33% of the patients had chronic stress. Compared with patients without chronic stress, higher expression levels of adrenoceptor beta 2 and PlexinA1 were observed in patients with chronic stress. The tumor size in mice under CUMS was significantly increased compared with the control mice. Adrenoceptor beta 2, PlexinA1, N-cadherin, and alpha-smooth muscle actin, as well as Ki67 were highly expressed in the tumors of CUMS group. However, E-cadherin was lowly expressed in the tumors of CUMS group. Importantly, chemical sympathectomy with 6-hydroxydopamine or treatment with a selective β2 adrenergic receptor antagonist (ICI118,551) could reverse these effects. Our findings suggest that chronic stress plays an important role in GC progression and there is a potential for blocking the epinephrine-β2AR/PlexinA1 pathway in the treatment of GC.

Objective Chemotherapy resistance and side effects are important reasons for the failure of lung cancer treatment. Therefore, finding new sensitizers for chemotherapeutic drugs is an urgent problem to be solved.Method In this study, A549 cells were given different pharmacological interventions, including control, cisplatin, DMY and the combination of cisplatin and DMY. The level of cell proliferation and apoptosis were detected by MTT assay and Flow cytometry AV/PI double staining. Transwell assay was adopted to detect the ability of migration and invasion of A549 cells. Western blot analyzed the expression of protein about proliferation, apoptosis, migration, and invasion.Results The present study denoted that DMY strengthened the effect of cisplatin on the inhibition of proliferation in lung cancer A549 cells. Meanwhile, DMY promoted cisplatin induced apoptosis of A549 cells. Further, DMY combined with cisplatin can synergistically inhibit the migration and invasion of A549 cells. Western blotting results showed that the expression of E-cadherin was significantly increased in the combination group compared to cisplatin group, while, the expression of N-cadherin, matrix metalloproteinase MMP 2, MMP 9 and Smads proteins (p-SMAD 3, t-SMAD 3, t-SMAD 4), were significantly decreased in the combination group.Conclusion Low dosage of DMY can significantly enhance the effect of cisplatin treatment in lung cancer cells, and its mechanism may be related to the induction of apoptosis, inhibition of proliferation, migration and invasion, which is expected to be a low-toxic and efficient chemosensitizer for lung cancer treatment.