Caterpillar Fungus Compound Blocks Cancer Growth Signals Within 30 Minutes

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMNov 15 2024

Cordycepin, derived from the Cordyceps or Ophiocordyceps fungus, has long been studied for its therapeutic potential, especially in cancer treatment. In a recent study published in FEBS Letters,  a research team from the University of Nottingham examined the ability of cordycepin to inhibit cell growth by impacting growth factor signaling pathways, which are essential for cell proliferation and survival.

Specifically, the researchers investigated how the active form of cordycepin, cordycepin triphosphate, interferes with key pathways such as various protein kinase pathways across multiple cell lines.

The findings suggest that cordycepin could serve as a promising therapeutic agent for blocking critical growth signaling pathways in diverse types of cancers.

​​​​​​​Study: Cordycepin generally inhibits growth factor signal transduction in a systems pharmacology study. Image Credit: annguyen87/Shutterstock.com

Background

Cordycepin is a natural compound derived from the caterpillar fungus belonging to the family Ophiocordycipitaceae. It has gained substantial interest for its potential value in cancer therapy due to its ability to impact cell growth and survival pathways.

Cordycepin’s primary mechanism of action is through its metabolite, cordycepin triphosphate, which acts as a messenger ribonucleic acid (mRNA) polyadenylation inhibitor and is known for interfering with transcription.

Furthermore, previous studies have reported that cordycepin can disrupt the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathways — two pathways that are critical for cell proliferation, metabolism, and survival. These pathways are frequently overactive in various cancers, making them valuable targets in cancer therapy.

About the Study

In the present study, the researchers used a combination of bioinformatic analysis, quantitative polymerase chain reaction (PCR), and western blotting techniques to investigate the impact of cordycepin on growth factor signaling in different cell lines.

Cordycepin was applied to cells in a controlled tissue culture environment, where it was metabolized into cordycepin triphosphate, the active form of cordycepin.

Cultures of human breast cancer cell lines, mouse embryonic fibroblast cells, human embryonic kidney cells, and three more cell lines were used for the study.

The researchers treated the cells with varying concentrations of cordycepin and compared them to cells treated with known inhibitors of specific kinases in the MEK/ERK and PI3K/AKT/mTOR pathways.

The changes in phosphorylation states of key proteins in these pathways were then measured, as phosphorylation states are indicators of pathway activation or suppression. Additionally, the researchers performed polyribosome profiling to assess the effect of cordycepin on the mRNA translation processes mediated by the mTOR pathway.

The study also included gene expression profiling to understand the transcriptional changes induced by cordycepin across different cell lines.

It utilized ingenuity pathway analysis (IPA) to identify the affected canonical or established pathways and upstream regulators involved in cancer and growth. In some cases, the cells were pre-treated with pentostatin, which is an adenosine deaminase inhibitor, to enhance the intracellular levels of cordycepin triphosphate and increase sensitivity to cordycepin.

Additionally, the researchers employed a combination of molecular biology techniques to ensure that observed effects were due to cordycepin’s impact on the targeted pathways rather than unrelated cellular stress responses.

This approach allowed for a comprehensive examination of how cordycepin influences growth factor-induced signaling and gene expression across a diverse range of cell types.

Major Findings

The results showed that cordycepin significantly inhibited growth factor signaling in multiple cell lines, particularly through the MEK/ERK and PI3K/AKT/mTOR pathways. This inhibition was observed through the reduction in the phosphorylation of key pathway components, which also effectively suppressed cellular responses to growth factors.

By comparing the effects of cordycepin with those of specific kinase inhibitors, the researchers also showed that cordycepin’s impact is similar to PI3K inhibition, suggesting that the PI3K/AKT/mTOR pathway might be its primary target.

In the fibroblast cells, cordycepin markedly repressed serum-induced gene expression, especially for genes involved in growth, such as MYC and FOS proto-oncogenes.

The researchers also noted that similar effects were observed in breast cancer cell lines, where cordycepin reduced the survival, proliferation, and migration of human breast cancer cells.

Interestingly, when combined with pentostatin, the effects of cordycepin on cell growth inhibition were more pronounced, supporting the role of cordycepin triphosphate as the active metabolite.

Furthermore, the study showed that cordycepin rapidly decreased the association between polyribosomes and mRNAs, indicating that it could impact mRNA translation, possibly through mTOR pathway inhibition. This finding was further supported by the downregulation of translation-associated mRNAs observed in the polysome profiling.

Moreover, the pathway analysis consistently indicated that growth factors such as epidermal growth factor (EGF) and cytokine signaling were the primary targets of cordycepin’s inhibitory effects, highlighting its action on cancer-related signaling processes.

Conclusions

Overall, the study confirmed cordycepin’s broad ability to inhibit growth factor-driven signaling across multiple cell types and cancer cell lines, especially through PI3K/mTOR pathways.

These findings highlighted the potential applications of cordycepin as an anticancer agent, especially for cancer types that were reliant on PI3K/AKT/mTOR and similar protein kinase pathways for growth and survival.