Withaferin A as a potent regulator of hepatocellular carcinoma

Varsha D. Shiragannavar’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews.

Varsha is currently a second year Ph.D. student working in the lab of Dr. Prasanna K. Santhekadur at Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR) Laboratory, Department of Biochemistry, JSS Medical College, JSS AHER, Mysuru. Her doctoral studies is primarily focused on investigating the role of RNA-induced silencing complex and associated proteins in the progression of non-alcoholic fatty liver disease and hepatocellular carcinoma. She is trying to understand the molecular/cellular process on how RISC complex genes and protein are regulated when treated with many dietary natural products. Here, Varsha talks about her work titled “Withaferin A Acts as a Novel Regulator of Liver X Receptor-a in HCC” published as first author in Front Oncol 2021.

How would you explain your paper’s key results to the non-scientific community?

Over the past two decades rapid changes in the lifestyle around the globe including India having a significant impact on liver diseases such as Nonalcoholic fatty liver disease (NAFLD), and associated Hepatocellular Carcinoma (HCC). Recent reports from Zydus Cadila pharmaceutical company suggested that Indians around 400 million are suffering from Fatty liver. Currently, there are one or two drugs available in the market to treat NAFLD and HCC. Therefore, this study has an urgent need for Pharmaceutical Industries and clinical research.

The famous quote by the Greek physician Hippocrates states that “Let food be your medicine and let medicine be your food” has stood the test of time. Natural dietary compounds are gaining increasing popularity in recent years as pharmaceutical drugs due to their pleiotropic effects and multifaceted beneficial properties with less or no side effects. Ashwagandha/ Withania somnifera is not new to Indians and is one of the most important plants profoundly used in ancient Ayurvedic medicine. This plant used as a medicine for the past 3,000 years, and this products, including, roots, leaves, berries and stem have been used as rejuvenator drink/tonic, anti-oxidant and paste to treat wounds. Also, used to treat stress, anxiety, aging, autoimmune diseases, inflammation, and many other diseases. Withaferin A is a steroidal lactone isolated from Withania somnifera plants, belongs to withanolide family of compounds. Withaferin A is one among more than 50 chemicals identified in Withania somnifera extracts which have medicinal properties.

Figure 1. Schematic representation of Withaferin A-mediated regulation of LXR-α and NFҡB signaling in HCC.

In this study, we demonstrated that Withaferin A, a natural compound has inhibitory effects on aggressive behaviour of HCC cells and how they are activating nuclear receptor LXR- α. Interestingly, withaferin A decelerates various cancer hallmarks such as proliferation, migration, and invasion. Also, downregulate anchorage-independent cell growth ability, LXR-α mediated NF-ҡB activation.

Hence, we think that translating the use of Withaferin A for the treatment of HCC in humans holds great promise near future.

“Our work presents a possible novel mechanistic model that Withaferin A may negatively regulate NF-kB transcription factor via activating LXR- α”

What are the possible consequences of these findings for your research area?

The ligand molecule withaferin A affects LXR- α was studied, and its role in inhibiting HCC was promising. However, molecular interactions of Withaferin A with various genes or transcription factors were not known. Our work presents a possible novel mechanistic model that Withaferin A may negatively regulate NF-kB transcription factor via activating LXR- α (Figure 1). Withaferin A acts similarly to the already approved drug for NAFLD, Saroglitazar an Indian origin drug. Saroglitazar widely described acts on PPARα/γ whereas, withaferin A acts on another nuclear factor called LXR-α. Reports suggested that LXR-α activation potentiates sorafenib sensitivity in HCC cells.  Our finding shows that withaferin A activates LXR-α, therefore Withaferin A has all the potential to sensitize HCC cells in presence of sorafenib. Withaferin A also has the potential to kill HCC cells via activating LXR-α and inhibiting NF-kB.

What was the exciting moment (eureka moment) during your research?

Eureka moment for me was when we found out that Withaferin A induces LXR- α target genes. On the other hand, when we found Withaferin A inhibits NF-kB target genes via LXR-α. These two findings were eureka moments for me!

What do you hope to do next?

We now know that Withaferin A has decelerated many hallmarks of cancer through this study. Further, we will explore the possible role of RNA-induced silencing complex in non-alcoholic fatty liver disease, and hepatocellular carcinoma development and progression. Later, we intended to investigate molecular interaction using dietary natural compounds on inflammatory signalling pathways, mRNA regulation, protein expression, translational modification in in vitro and in vivo. Based on our results from in vivo diet induced animal model of obesity and NAFLD and HCC xenograft studies, we will be planning to go further for phase1 clinical trials.

Where do you seek scientific inspiration?

I have always been fascinated by how life exists on earth. This was the reason why I chose biology as the main subject during my education. After my masters, I grabbed the opportunity to do research under the guidance of Dr. Prasanna K. Santhekadur at JSS Medical College, JSS AHSR, Mysuru. I have always been inspired by him for his motivational and scientific talks and discussions to actively pursue new ideas and implement them. He has always taught us the importance of “Positive Imaging in life as well as in academic research”. This drives me to work harder and smarter with great values and positive thinking. We have good lab culture and healthy competition to successfully complete my doctoral research.

How do you intend to help Indian science improve?

Today’s children are tomorrow’s future of India. Enlightening the young minds with the current trends in science and encouraging them to choose the field is essential. We are planning to conduct interactive sessions (Talk to a Scientist program) with school children introducing them to the whole new world of science. As a researcher, I would like to contribute to the mankind by developing novel drugs to treat NAFLD and liver cancer.

Reference

Shiragannavar VD, Gowda NGS, Kumar DP, Mirshahi F and Santhekadur PK (2021) Withaferin A Acts as a Novel Regulator of Liver X Receptor-a in HCC. Front. Oncol. 10:628506.

Email ID: varsha.ds08@gmail.com

Edited by: Govinda Raju Yedida (Volunteer, Bio Patrika)

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