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Cucurbitacin-B inhibits cancer cell migration by targeting mortalin and HDM2: computational and in vitro experimental
He Huifu1,2, Seyad Shefrin3, Shi Yang4,2
1Graduate School of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan.
Abstract:
Cancer metastasis, a highly complex process wherein cancer cells move from the primary site to other sites in the body, is a major hurdle in its therapeutics. A large array of synthetic chemotherapeutic molecules used for the treatment of metastatic cancers, besides being extremely expensive and unaffordable, are known to cause severe adverse effects leading to poor quality of life (QOL) of the patients. In this premise, natural compounds (considered safe, easily available and economic) that possess the potential to inhibit migration of cancer cells are deemed useful and hence are on demand. Cucurbitacin-B (19-(10→9β)-abeo-10-lanost-5-ene triterpene, called Cuc-B) is a steroid mostly found in plants of Cucurbitaceae family. It has been shown to possess anticancer activity although the molecular mechanism remains poorly defined. We present evidence that Cuc-B has the ability to interact with mortalin and HDM2 proteins that are enriched in cancer cells, suppress wild type p53 function and promote cancer cell migration. Computational analyses showed that Cuc-B interacts with mortalin similar to MKT077 and Withanone, both have been shown to reactivate p53 function and inhibit cell migration. Furthermore, Cuc-B interacted with HDM2 similar to Y30, a well-known inhibitor of HDM2. Experimental cell and molecular analyses demonstrated the downregulation of several proteins, critically involved in cell migration in Cuc-B (low non-toxic doses)-treated cancer cells and exhibited inhibition of cell migration. The data suggested that Cuc-B is a potential natural drug that warrants further mechanistic and clinical studies for its use in the management of metastatic cancers.Communicated by Ramaswamy H. Sarma.
Insights
Cucurbitacin-B, a natural compound, inhibits cancer cell migration by interacting with mortalin and HDM2 proteins. This natural compound shows potential as a therapeutic for metastatic cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cancer metastasis is a significant challenge in cancer treatment, often requiring expensive and toxic synthetic chemotherapeutics.
- Natural compounds offer a safer, more accessible, and economical alternative for inhibiting cancer cell migration.
- Cucurbitacin-B (Cuc-B), a triterpene from the Cucurbitaceae family, exhibits anticancer properties, but its mechanism of action is not well-defined.
Purpose of the Study:
- To investigate the molecular mechanisms by which Cuc-B affects cancer cell migration.
- To explore the interaction of Cuc-B with mortalin and HDM2 proteins, which are implicated in cancer progression.
- To evaluate the potential of Cuc-B as a natural therapeutic agent for metastatic cancers.
Main Methods:
- Computational analyses to predict Cuc-B's interaction with mortalin and HDM2.
- Experimental cell and molecular analyses to assess protein expression and cell migration.
- Treatment of cancer cells with low, non-toxic doses of Cuc-B.
Main Results:
- Cuc-B was found to interact with mortalin and HDM2 proteins, similar to known modulators of these proteins.
- Cuc-B suppressed wild-type p53 function and promoted cancer cell migration.
- Experimental data confirmed that Cuc-B downregulates proteins involved in cell migration and inhibits cancer cell migration.
- Low, non-toxic doses of Cuc-B were effective in inhibiting cancer cell migration.
Conclusions:
- Cucurbitacin-B demonstrates the ability to inhibit cancer cell migration through interactions with mortalin and HDM2.
- The findings suggest Cuc-B is a promising natural compound for managing metastatic cancers.
- Further mechanistic and clinical studies are warranted to validate Cuc-B as a potential therapeutic drug.
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