Nobiletin Induces Ferroptosis in Human Skin Melanoma Cells Through the GSK3β-Mediated Keap1/Nrf2/HO-1 Signalling Pathway.

Senling Feng,Yifeng Zeng,Quanzhi Liu,Yongheng Zhou,Hongliang Huang,Kaikai Huang,Wenting Zhu,Ying Lin,Zhongwen Yuan,Baoying Liang,Shanshan Han

doi:10.3389/fgene.2022.865073

Abstract

Melanoma is an aggressive malignant skin tumour with an increasing global incidence. However, current treatments have limitations owing to the acquired tumour drug resistance. Ferroptosis is a recently discovered form of programmed cell death characterised by iron accumulation and lipid peroxidation and plays a critical role in tumour growth inhibition. Recently, ferroptosis inducers have been regarded as a promising therapeutic strategy to overcome apoptosis resistance in tumour cells. In this study, we reported that nobiletin, a natural product isolated from citrus peel, and exhibited antitumour activity by inducing ferroptosis in melanoma cells. Subsequently, we further explored the potential mechanism of nobiletin-induced ferroptosis, and found that the expression level of glycogen synthase kinase 3β (GSK3β) in the skin tissue of patients with melanoma was significantly reduced compared to that in the skin of normal tissue. Additionally, nobiletin increased GSK3β expression in melanoma cells. Moreover, the level of Kelch-like Ech-associated protein-1 (Keap1) was increased, while the level of nuclear factor erythroid 2-related factor 2 (Nrf2), and haem oxygenase-1 (HO-1) was decreased in nobiletin-treated melanoma cells, suggesting that the antioxidant defence system was downregulated. Furthermore, knockdown of GSK3β significantly reduced nobiletin-induced ferroptosis and upregulated the Keap1/Nrf2/HO-1 signalling pathway, while the opposite was observed in cells overexpressing GSK3β. In addition, molecular docking assay results indicated that nobiletin showed strong binding affinities for GSK3β, Keap1, Nrf2, and HO-1. Taken together, our results demonstrated that nobiletin could induce ferroptosis by regulating the GSK3β-mediated Keap1/Nrf2/HO-1 signalling pathway in human melanoma cells. Hence, nobiletin stands as a promising drug candidate for melanoma treatment with development prospects.

Highlights

Melanoma is a highly aggressive skin malignancy that arises from the malignant proliferation of melanocytes (Eddy and Chen, 2020)
These results suggest that glycogen synthase kinase 3β (GSK3β) mediates the regulation of the Kelch-like Ech-associated protein-1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/haem oxygenase-1 (HO-1) signalling pathway in nobiletin-treated melanoma cells
We report that the natural product nobiletin exhibits antitumour activity by triggering ferroptosis in human skin melanoma cells

Summary

Introduction

Melanoma is a highly aggressive skin malignancy that arises from the malignant proliferation of melanocytes (Eddy and Chen, 2020). Melanoma is often successfully treated with surgery when it is detected at an early stage (Scala et al, 2019). No effective treatments are available for advanced or metastatic melanoma. Targeted therapy and immunotherapy have been used for the treatment of melanoma and have led to improved clinical outcomes, their high cost and the development of tumour resistance to these treatments limit their clinical application (Falcone et al, 2020; Swayden et al, 2020; Matias et al, 2021). The identification and development of novel, effective, and accessible therapeutic approaches for melanoma that overcome the limitations of current treatments is urgently needed

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