Withaferin A activates TRIM16 for its anti-cancer activity in melanoma

Zsuzsanna Nagy,Daniel R Carter,Owen Tan,Mika Herath,Glenn M Marshall,Wing Tsang,Belamy B Cheung,Fatima Shadma,Olivia C Ciampa

doi:10.1038/s41598-020-76722-x

Abstract

Although selective BRAF inhibitors and novel immunotherapies have improved short-term treatment responses in metastatic melanoma patients, acquired resistance to these therapeutics still represent a major challenge in clinical practice. In this study, we evaluated the efficacy of Withaferin A (WFA), derived from the medicinal plant Withania Somnifera, as a novel therapeutic agent for the treatment of melanoma. WFA showed selective toxicity to melanoma cells compared to non-malignant cells. WFA induced apoptosis, significantly reduced cell proliferation and inhibited migration of melanoma cells. We identified that repression of the tumour suppressor TRIM16 diminished WFA cytotoxicity, suggesting that TRIM16 was in part responsible for the cytotoxic effects of WFA in melanoma cells. Together our data indicates that WFA has potent cytopathic effects on melanoma cells through TRIM16, suggesting a potential therapeutic application of WFA in the disease.

Highlights

Selective BRAF inhibitors and novel immunotherapies have improved short-term treatment responses in metastatic melanoma patients, acquired resistance to these therapeutics still represent a major challenge in clinical practice
We have shown that high TRIM16 protein expression is associated with favourable outcome in melanoma patients with stage III disease[13]
Withaferin A (WFA) has increased cytotoxicity for melanoma cells compared with fibroblast cell lines

Summary

Introduction

Selective BRAF inhibitors and novel immunotherapies have improved short-term treatment responses in metastatic melanoma patients, acquired resistance to these therapeutics still represent a major challenge in clinical practice. We evaluated the efficacy of Withaferin A (WFA), derived from the medicinal plant Withania Somnifera, as a novel therapeutic agent for the treatment of melanoma. We identified that repression of the tumour suppressor TRIM16 diminished WFA cytotoxicity, suggesting that TRIM16 was in part responsible for the cytotoxic effects of WFA in melanoma cells. Together our data indicates that WFA has potent cytopathic effects on melanoma cells through TRIM16, suggesting a potential therapeutic application of WFA in the disease. Withaferin A (WFA), a steroidal lactone extracted from Withania somnifera, has been described as a potential anti-cancer drug both in vivo and in vitro[3,4] through its diverse anti-tumour properties and low cytotoxicity to non-malignant cells. The above detailed evidence suggested that increased TRIM16 expression is a potential molecular target for the treatment of melanoma

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