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

Abstract

Diabetes mellitus (DM) is associated with an increased risk and progression of cholangiocarcinoma (CCA). High glucose underlying the association between DM and CCA by modulating the intracellular signaling has been demonstrated. However, the effects of DM and hyperglycemia on cell cycle machineries and progression of CCA remain elucidated. CCA cells, KKU-213A and KKU-213B were cultured in normal (NG, 5.6 mM) or high glucose (HG, 25 mM) resembling euglycemia and hyperglycemia. Western blotting was used to determine expressions of cell cycle machineries in CCA cells. The expression of cyclin A in CCA tissues from patients with or without hyperglycemia was determined by immunohistochemistry. Pan-cyclin dependent kinases (CDKs) inhibitor and silencing of cyclin A expression were investigated as a possible modality targeting CCA treatment in patients with DM. High glucose induced expression of cell cycle machinery proteins in both CCA cells. Among these, cyclin A was consistently and significantly upregulated. Nuclear cyclin A was significantly increased in tumor tissues from CCA patients with hyperglycemia and was significantly associated with post-operative survival of shorter than 5 mo. Silencing cyclin A expression sensitized CCA cells to pan-CDKs inhibitor, suggesting the combined treatment as an alternative approach for treatment of CCA patients with DM.

Acknowledgments

C. Saengboonmee received a fellowship from Prince Mahidol Award Youth Program of the year 2018 (PMAYP-10612) from Prince Mahidol Award Foundation under the royal patronage of His Majesty the King of Thailand and currently a visiting scientist with the co-support from Prof. Piotr Sicinski, Dana-Farber Cancer Institute, and Department of Genetics, Harvard Medical School, Boston, MA, USA. We are grateful to Dr. Siwanon Jirawatnotai, Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, for providing antibodies for a revision of manuscript. We thank Prof. James A. Will for editing the manuscript via the KKU Publication Clinic, Khon Kaen University, Thailand.

Author Contributions

Conceptualization: CS, WS, SW; Methodology and Investigation: CS, MD, SS; Formal analysis: CS, MD, SS; Visualization: CS, MD; Resource: KS; Funding Acquisition; KS, WS, SW; Writing-Original Draft: CS; Writing-Review & Editing: CS, WS, SW. All authors contributed to critically review and approve the final version of manuscript.

Declaration of Interest Statement

The authors declare no conflict of interest.

Additional information

Funding

This work was financially supported by a research grant from Khon Kaen University for S. Wongkham (I62-01-02).