Introduction Globally lung cancer has the

Introduction Globally, lung cancer has the highest morbidity and mortality rates of all types of cancer, with 1.5 million patients newly diagnosed annually [1]. Approximately 85% of lung cancer cases are non-small cell lung cancer (NSCLC) [2]. The first-line treatment for NSCLC is surgical resection combined with radiotherapy and chemotherapy [1,3]. Despite significant improvements in the efficacy of chemotherapy drugs and the availability of molecularly targeted therapy drugs in clinical practice in the past decade, the 5-year survival rate of patients with NSCLC is still low [1,3]. Tumor metastasis is a critical factor in the low survival rate for patients with NSCLC, which is associated with a variety of factors, including angiogenesis [4,5], epithelial-mesenchymal transition (EMT) [[6], [7], [8]], and the migration [9] and invasion [10,11] of tumor cells. The activation of the CXCR4/SDF1 axis plays an important role in the process of NSCLC metastasis [[12], [13], [14]]. Despite the development of small-molecule drugs with greater specificity and efficacy against tumors, the side effects of chemotherapy drugs are severe, limiting their clinical application. Natural plant extracts from a wide range of sources may have fewer side effects and higher tolerability and have provided novel insights into cancer treatment in recent years [15]. Hesperidin is a natural flavonoid glycoside compound, occurring in orange peel and other citrus species, that is widely used in Chinese herbal medicine [16]. It was previously demonstrated to induce anticancer activity through the promotion of apoptosis [[17], [18], [19], [20], [21]]. Furthermore, hesperidin affected the expression of MMP family members and EMT-related proteins to inhibit cell invasion, resulting in anti-cancer activity [[22], [23], [24]]. In vitro and in vivo studies have demonstrated that hesperidin enhances antioxidant activity, thus inhibiting tumor development [25,26]. Our previous studies have identified that hesperidin promotes the apoptosis of A549 NSCLC PJ34 pathway by regulating the proteins in the mitochondrial apoptosis pathway and modulating the expression of cell cycle-related molecules, without any negative effects on BEAS-2B human normal lung epithelial cells [21]. However, data regarding the effect of hesperidin on NSCLC cells is incomplete. Hence, we investigated the SDF-1/CXCR-4 signaling pathway and EMT process to understand the underlying mechanisms of the effect of hesperidin. The reported results may provide the foundation for the development of hesperidin as a safer and more effective anticancer drug for NSCLC.
Materials and methods
Results
Discussion Cell migration is a normal physiological process, required for chemotaxis of white blood cells and directional movement of cells from other tissues [27,28]. However, in tumor tissue, the metastatic ability of malignant tumor cells is significantly associated with the likelihood of patient death [29]. Previous studies have shown that the activation of tumor cell migration is associated with the activity of the SDF-1/CXCR-4 signaling pathway [[30], [31], [32]]. The SDF-1-activated CXCR-4 receptor, which is folded and delivered to the cell surface by HSP90, induces a phosphorylation cascade, leading to actin reorganization and subsequent cell migration [33]. In the present study, we report that the SDF-1α-mediated enhancement of migratory ability in A549 cells could be inhibited by treatment with the SDF-1/CXCR-4 specific inhibitor AMD3100 or hesperidin. Based on the results of ELISA and western blotting, we confirmed that hesperidin could significantly reduce the protein expression of CXCR-4 and the level of SDF-1 secreted from A549 cells. Thus, hesperidin may potentially inhibit tumor cell metastasis through a complicated process. Interestingly, a recent study by Li et al. found that the natural product Kongensin A was a non-canonical HSP90 inhibitor that blocked RIP3-dependent necroptosis, providing a new perspective on the matter [34]. This informed our hypothesis that the inhibitory effect of hesperidin on the migratory and invasive capabilities of human NSCLC cells may be mediated by the regulation of SDF-1 and downstream molecule expression and activity, through target proteins such as HSP90, although further study is required prior to the development of hesperidin as a therapeutic drug.