Abstract
Apigenin, a nonmutagenic flavonoid, has been found to have antitumor properties and is therefore particularly relevant for the development of chemotherapeutic agents for cancers. In this study, time- and dose-dependent cell viability and cytotoxicity were assessed to determine the effects of apigenin on A2058 and A375 melanoma cells. Melanoma cells were pretreated with different concentrations of apigenin and analyzed for morphological changes, anoikis induction, cell migration, and levels of proteins associated with apoptosis. Apigenin reduced integrin protein levels and inhibited the phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK1/2), which induce anoikis in human cutaneous melanoma cells. Apigenin exhibited dose-dependent inhibition of melanoma cell migration, unlike untreated controls. Furthermore, apigenin treatment increased apoptotic factors such as caspase-3 and cleaved poly(ADP-ribose) polymerase in a dose-dependent manner, demonstrating the metastasis of melanoma cells. Our results provide a new insight into the mechanisms by which apigenin prevents melanoma metastasis by sensitizing anoikis induced by the loss of integrin proteins in the FAK/ERK1/2 signaling pathway. These findings elucidate the related mechanisms and suggest the potential of apigenin in developing clinical treatment strategies against malignant melanoma.
Highlights
Melanoma is the most aggressive form of skin cancer, causing more than 90% of the deaths resulting from this disease [1]
We investigated the effect of apigenin on the expression of the integrin subunits α4, α5, αV, and β3 in melanoma cell lines and their contributions in the phosphorylation of focal adhesion kinase (FAK) and ERK1/2
We have demonstrated that apigenin significantly inhibited the growth of melanoma cells and induced apoptosis
Summary
Melanoma is the most aggressive form of skin cancer, causing more than 90% of the deaths resulting from this disease [1]. Metastasis is a multistep and complex process It involves the detachment of carcinoma cells from the originated sites, degradation of the extracellular matrix (ECM), survival in the vascular system, invasion of surrounding tissues, cell adhesion, and proliferation in distant sites in the body [3]. Various types of intracellular signaling processes, such as proliferation, differentiation, invasion, metastasis, apoptosis, and anoikis are mostly influenced by Integrins [5,6,7]. ERK1/2, a subfamily of the mitogen-activated protein kinases (MAPKs), is one of the best characterized intracellular signaling pathways, which plays a crucial role in regulating the invasion and metastasis of melanoma [12]. We report that apigenin induces anoikis, a type of apoptosis induced by the loss of integrin-mediated cell matrix contact. We tried to explain the possible molecular mechanisms involved in the process
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