Withaferin A Acts as a Novel Regulator of Liver X Receptor-α in HCC.

Varsha D Shiragannavar,Nirmala G Sannappa Gowda,Faridoddin Mirshahi,Divya P Kumar,Prasanna K Santhekadur

doi:10.3389/fonc.2020.628506

Varsha D Shiragannavar, Nirmala G Sannappa Gowda + Show 3 more

Open Access

https://doi.org/10.3389/fonc.2020.628506

Copy DOI

Abstract

Withaferin A, a steroidal lactone derived from the Withania somnifera plant has been known for its anti-cancerous effects on various types of cancer cells. However, its effect on the hallmarks of cancer such as proliferation, migration, invasion, and angiogenesis is still poorly understood. The antitumor property of Withaferin A and its molecular mechanism of action on hepatocellular carcinoma (HCC) cells is not yet completely established. In this study, we aimed to elucidate the novel molecular function of Withaferin A on HCC cells and its effect on various gene expression. Our results clearly showed that Withaferin A treatment to HCC cells inhibited proliferation, migration, invasion, and anchorage-independent growth. Further, we explored the Withaferin A target genes by blotting human angiogenesis, and cytokine arrays using conditioned media of Withaferin A treated QGY-7703 cells. We found that many of Nuclear factor kappa B (NF-κB), angiogenesis and inflammation associated proteins secretion is downregulated upon Withaferin A treatment. Interestingly, all these genes expression is also negatively regulated by nuclear receptor Liver X receptor-α (LXR-α). Here, we explored a novel mechanism that Withaferin-A activated LXR-α inhibits NF-κB transcriptional activity and suppressed the proliferation, migration, invasion, and anchorage-independent growth of these HCC cells. All these data strongly confirmed that Withaferin A is a potent anticancer compound and suppresses various angiogenesis and inflammatory markers which are associated with the development and progression of HCC. This beneficial and potential therapeutic property of Withaferin A will be very useful for the treatment of HCC.

Highlights

Hepatocellular Carcinoma is one of the menacing and most common types of primary liver cancers and it is the third most leading cause of cancer-related deaths across the globe [1, 2]
We found that Withaferin A modulates the secretion of angiogenic factors and inflammatory cytokines and inhibits proliferation, migration, invasion, and anchorage-independent growth of these cells through the activation of Liver X receptor-a (LXR-a) and LXR-a mediated suppression of Nuclear factor kappa B (NF-kB) transcription factor
We explored the therapeutic potential of Withaferin A on proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells

Summary

Introduction

Hepatocellular Carcinoma is one of the menacing and most common types of primary liver cancers and it is the third most leading cause of cancer-related deaths across the globe [1, 2]. There are various signaling pathways associated with the initiation, development, and progression of hepatocellular carcinoma [5]. Some of these signaling pathways are involved in proliferation, invasion, migration, anchorage-independent growth, and resistance to apoptotic stimuli [6]. Targeting these pathways with suitable and specific drugs to treat HCC is the urgent need of the hour

Objectives

Methods

Results

Conclusion