Inhibiting the actions of cyclin A and cyclin-dependent kinase 2 (CDK2) significantly reduces the proliferation of cholangiocarcinoma cells in culture, found a new study published in the journal Nutrition and Cancer.

This could represent a potential new therapeutic approach for patients with cholangiocarcinoma who also have diabetes mellitus, a disease characterized by high levels of plasma glucose.

Previous research has shown that diabetes mellitus is a risk factor that promotes cholangiocarcinoma. The exact mechanism of how high plasma glucose levels may induce the proliferation and metastatic potential of cholangiocarcinoma cells is not well understood. However, it is thought that it could be the result of the action of cyclin family proteins. Therefore, targeting cyclin-dependent kinases (CDK) could improve outcomes in cholangiocarcinoma.


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Learn more about cholangiocarcinoma etiology

In order to elucidate the underlying mechanism of how diabetes mellitus increases the risk of progression of cholangiocarcinoma, a team of researchers led by Sopit Wongkham, PhD, of Khon Kaen University in Thailand grew cholangiocarcinoma cells in culture under normal and high glucose conditions. They then used Western blotting to analyze the expression of proteins involved in the cell cycle machinery. They found that cyclin A was consistently and significantly upregulated in high glucose conditions.

The researchers then analyzed the expression of cyclin A in cholangiocarcinoma tissue obtained from patients with and without hyperglycemia and found that cyclin A expression was significantly increased in tumor tissues from patients with hyperglycemia. This was significantly associated with postoperative survival of shorter than 5 months. 

The researchers also showed that silencing cyclin A expression in cholangiocarcinoma cells significantly reduced the proliferation of cholangiocarcinoma cells. 

“This study reveals the significance of cyclin A in [high glucose] condition,” the researchers wrote, adding that silencing cyclin A expression and inhibiting CDKs could be a therapeutic alternative for cholangiocarcinoma patients with diabetes mellitus. 

The effect of high glucose and cyclin A expression on cholangiocarcinoma should now be confirmed in in vivo models, according to the authors.

Reference

Saengboonmee C, Detarya M, Sangkhamanon S, Sawanyawisuth K, Seubwai W, Wongkham S. High glucose induced upregulation of cyclin A associating with a short survival of patients with cholangiocarcinoma: a potential target for treatment of patients with diabetes mellitus. Nutr Cancer. Published online August 6, 2021. doi:10.1080/01635581.2021.1961830