UVA Irradiation Enhances Brusatol-Mediated Inhibition of Melanoma Growth by Downregulation of the Nrf2-Mediated Antioxidant Response.

Mei Wang,Chunxiang Bian,Xuemei Jiang,Guangwei Shi,Ping Ji,Julia Li Zhong,Wei Li,Jörg W Bartsch,Yingying Guo,Xiao Huang,Yan Wu,Muhammad Farrukh Nisar

doi:10.1155/2018/9742154

Abstract

Brusatol (BR) is a potent inhibitor of Nrf2, a transcription factor that is highly expressed in cancer tissues and confers chemoresistance. UVA-generated reactive oxygen species (ROS) can damage both normal and cancer cells and may be of potential use in phototherapy. In order to provide an alternative method to treat the aggressive melanoma, we sought to investigate whether low-dose UVA with BR is more effective in eliminating melanoma cells than the respective single treatments. We found that BR combined with UVA led to inhibition of A375 melanoma cell proliferation by cell cycle arrest in the G1 phase and triggers cell apoptosis. Furthermore, inhibition of Nrf2 expression attenuated colony formation and tumor development from A375 cells in heterotopic mouse models. In addition, cotreatment of UVA and BR partially suppressed Nrf2 and its downstream target genes such as HO-1 along with the PI3K/AKT pathway. We propose that cotreatment increased ROS-induced cell cycle arrest and cellular apoptosis and inhibits melanoma growth by regulating the AKT-Nrf2 pathway in A375 cells which offers a possible therapeutic intervention strategy for the treatment of human melanoma.

Highlights

Malignant melanoma (MM) is one of the most prevalent cancers in the Western world and is a highly aggressive dermatological malignancy associated with poor patient prognosis
We have found that RNA interference of Nuclear factor E2-related factor 2 (Nrf2) in human skin fibroblasts increases long wave UVA(320–400 nm) mediated damage [34], while Hirota et al showed that Nrf2−/− 3T3 mouse fibroblasts exert increased UVA-mediated apoptosis and necrosis [35]
Western blot results showed that these doses of UVA irradiation induced the expression of Nrf2, heme oxygenase 1 (HO-1), and GSTP1 proteins, with slight induction of NAD(P)H:quinone oxidoreductase-1 (NQO1) protein (Figure 1(b))

Summary

Introduction

Malignant melanoma (MM) is one of the most prevalent cancers in the Western world and is a highly aggressive dermatological malignancy associated with poor patient prognosis. The majority of MM arise from congenital melanocytic nevi or are due to a family history of MM; in some cases, 50% MM can be associated with repeated intermittent sporadic ultraviolet (UV) exposure [1, 2], mostly UVB radiation plays a dominant role in the development of malignant melanoma, but the role of UVA is still unclear and controversial [3]. The progressive accumulation of genetic and environmental alterations causes disruption of homeostatic pathways, resulting in tumor cell invasion and lymphatic or haematogenous dissemination to distant sites [4]. Some reports showed that Nrf expression in melanoma is related to invasion thereby worsening melanoma-specific

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Conclusion