Cirsiliol Suppressed Epithelial to Mesenchymal Transition in B16F10 Malignant Melanoma Cells through Alteration of the PI3K/Akt/NF-κB Signaling Pathway.

Priyanka Prasad,Judit Hohmann,Andrea Vasas,Dona Sinha,Anupam Bishayee

doi:10.3390/ijms20030608

Abstract

Malignant melanoma is a highly aggressive form of skin cancer which has a propensity for metastasis. Epithelial mesenchymal transition (EMT) plays a primordial role in the progression of metastatic disease. Metastatic melanoma is resistant to conventional therapies. Hence, researchers have been exploring alternative approaches, including the utility of bioactive phytochemicals to manage metastatic disease. In the present study, we investigated the potential of cirsiliol, a flavonoid isolated from Centaurea jacea L., in modulating the aggressive behavior of B16F10 metastatic melanoma cells, including EMT, and associated molecular mechanisms of action. Cirsiliol was found to be effective in restraining the colony formation and migration of fibronectin-induced B16F10 metastatic melanoma cells. Cirsiliol inhibited the activity and expression of matrix metalloproteinase-9 (MMP-9). Cirsiliol also suppressed the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (also known as Akt)/nuclear factor-κB (NF-κB) signaling pathway which, in turn, caused upregulation of E-cadherin and downregulation of N-cadherin, Snail and Twist. Based on these results, cirsiliol may be considered a promising compound against EMT in the therapeutic management of malignant melanoma.

Highlights

Malignant melanoma is the most aggressive form of skin cancer
Since “cadherin switch” characterized by downregulation of E-cadherin and upregulation of N-cadherin is regarded as the hallmark of Epithelial mesenchymal transition (EMT), we investigated the status of E-cadherin and N-cadherin following FN treatment
The present study showed reduced nuclear expression of Snail by cirsiliol which was further supported by the retarded expression and activity of matrix metalloproteinase-9 (MMP-9) in FN-induced melanoma cells

Summary

Introduction

Malignant melanoma is the most aggressive form of skin cancer. About 91,270 new incidences of melanoma (55,150 in men and 36,120 in women) and 9320 deaths (5990 men and 3330 women) due to this disease are estimated to occur in the United States in 2018 [1]. The rates of melanoma have been rising for the last 30 years. It is represented by an overall mortality rate of around 20% and is responsible for 80% of global skin cancer-related deaths [2]. Early-stage melanoma can be effectively treated with surgery, but metastatic melanoma is highly resistant to conventional therapies [3]. The high rate of mortality is related to its chemotherapy resistance, aggressive behavior, and propensity to metastasize rapidly [4]

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Conclusion