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Ppar-γ for the Next Generation Cancer Chemotherapy

Ppar-γ for the Next Generation Cancer Chemotherapy

The blog delves into latest research on developing partial activators for PPAR-γ for better overall therapeutic effectiveness of lung cancer treatment.

Mrs. Sangeeta Ballav & Dr. Soumya Basu
April, 12 2023
2296

Preamble:

This is the story of a small protein molecule named Peroxisome proliferator-activated receptor-γ (PPAR-γ) in a cancer-affected body which is usually activated by certain specific compounds known as ligands. These ligands are categorized as weak, full and partial depending on their ability to activate the protein, PPAR-γ. Based on the activation process of PPAR-γ by these ligands, the growth of cancer cells is prevented and this helps in the elimination of tumor.

 

Welcome to the War of Activators!

The main characters of this story are:

Weak Activator - A chemical compound that exhibits weak effect for PPAR-γ protein activation.

Full Activator - A chemical compound that exhibits strong effect for PPAR-γ protein activation.

Peroxisome proliferator-activated receptor-γ, a.k.a PPAR-γ- small protein molecule which is  activated by ligands.

Somewhere within the body, the system senses a cancerous activity that may lead to a tumor formation!

A weak activator comes in contact with PPAR-γ. PPAR-γ is with a sensitive hat that recognizes the bond and signals further process.

Hey you guys! What is up with your signals? I haven’t received them properly to initiate the transcription process. If I don’t get activated then how will I suppress the tumor cells?’ asked PPAR-γ in frustration with a weak activator.

‘I am trying a lot to fit into your hat but I think you are very “selective” among us’ said the weak activator, who has managed to only partially attached to the hat of PPAR-γ.

‘That’s because your shape doesn’t match with my hat. It is covering only 50% of the space. This seems imperfect for activation, but still I will try to initiate the process.’ PPAR-γ sighed and tried starting the transcription process but the process ended up by activating the receptor with only 50% efficiency.

‘Oh no! These weak activators are not helping me to function properly; I may need to consult a strong activator’ said PPAR-γ in dilemma and approached the full activator.

Meanwhile the full activator pacified tensed PPAR-γ ‘Yeah, we can elicit a good and perfect response than the weak activator once we fit into your hat. We are much better than them.’

‘You perfectly fit in my hat! Now I can exquisitely process the transcription and suppress the tumor.’ PPAR-γ happily functioned for the cancer cells until he realized that it triggered something else in the cells. PPAR-γ got overexpressed by the full activator which led to other consequences and side effects.

This war continues among the activators in deciding who will fit better for PPAR-γ.

PPAR-γ, which is also called “The Multifaceted Factor” is an underlying ligand-activated transcription factor that highlights its importance in tumor suppression, apoptosis, DNA damage response and cell cycle arrest. The protein is an attractive target in today’s cancer research community due to its significant chemopreventive activities.

As the name suggests, it is activated by specific ligands such as endogenous, natural, or synthetic. However, the activation of this receptor persists in mere contradiction as the endogenous ligands and natural products have fewer effects which leads to weak stimulation. On the other hand, the synthetic ligands bind to PPAR-γ with high affinity which directs an over-activation process, serving as complete full activators.

A cartoon depicting PPAR-y esponse to various types of angonists

So, here is the question: Can the partial activation of PPAR-γ lead to tumor suppression?

This piece of the story describes the results of our latest research, which is based on developing partial activators for PPAR-γ for the better overall therapeutic effectiveness of lung cancer treatment.

 

Drug discovery is a lengthy and time-consuming process that undergoes several stages of testing and optimization. This encompasses the identification of targets, lead discovery, pre-clinical validation and clinical trials. Referring to this, the preliminary stage involves computational drug design where the rapid assessment of chemical libraries can be performed in order to guide and speed up the early-stage development of new active compounds.

Speaking of this notion, natural products, obtained directly from plants through the intake of food essentials, offer key ligands for triggering PPAR-γ. In particular, dietary flavonoids are known as promising candidates for cancer treatment and prevention.

These flavonoids naturally occur in grains, fruits, roots, vegetables, flowers, wine, bark, stems and tea. So, we have screened 8708 derivatives of flavonoids for targeting PPAR-γ through these computational approaches to obtain the new potential drug candidates and reported in the Journal of Biomolecular Structure and Dynamics, 2020.

Based on our results, we have designed and synthesized a few novel molecules. Our collaborators were a great help during the synthesis work. Further validation of these newly synthesized molecules was done through a series of in vitro experimentations which proved the efficacy of being a partial activator.

Strikingly, our synthesized molecules activated PPAR-γ with a partial expression as compared to the over-expressive level of synthetic ligands, which was used as a positive control. The work was successfully published in Advanced biology, 2023. Therefore, receptor-ligand binding selectivity has to do with what job the receptor performs for the cell.

Nevertheless, cancer alone cannot be grievous and deadly. These "sick" cells (so-called cancer cells) just grow too fast (forming a tumor), and take up the room that belonged to healthy cells (in our case, the lung cells). Let’s say there are other actors involved, driving the sick cells to grow rapidly and recklessly. One of them is epithelial-to-mesenchymal transition (EMT).

The term seems to fret because it has been linked to tumor progression via other networks. EMT is characterized by the transition of polarized immotile cobble-stoned epithelial cells to motile spindle-shaped mesenchymal cells. Speaking of the network, the signaling of transforming growth factor beta-1 (TGF-β1), a multifunctional cytokine, serves as a key player to have a greater impact on EMT.

This exhibits both morphological changes and molecular alterations. Therefore, we are also investigating the effectiveness of these partial activators on EMT, induced by TGF-β1 through partial activation of PPAR-γ.

In this aspect, we got encouraging results as our synthesized molecules have potently interrupted the most important regulator of EMT i.e. TGF-β1 on lung cancer cells. Our study has shown that the partial activators blocked the functional outcomes of EMT by stopping the changes in morphology and cellular migration of lung cancer cells.

The work was successfully published in Advanced biology, 2023. Well, this was not the end of the story. Although the synthesized partial activator did kill lung cancer cells, still more work on molecular aspects is yet to be done to develop a more economical anti-cancer drug.

The work was carried out by me under the supervision of Dr. Soumya Basu and Dr. Amit Ranjan in Cancer and Translational Research Centre at Dr.D.Y.Patil Biotechnology & Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune.

 

Authors: Mrs. Sangeeta Ballav & Dr. Soumya Basu

Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Research Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune, Maharashtra- 411033.

Email: sangeetaballav@gmail.com, soumya.basu@dpu.edu.in

Edited by: Dr. Viniti Vaidya

Microbial Diversity Research Centre, Biotechnology, Dr. D. Y. Patil Biotechnology & Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pimpri, Pune-411033. Email: viniti.vaidya@dpu.edu.in

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